Heterocycle substituted diphenyl leukotriene antagonists

ABSTRACT

The invention relates to novel heterocycle substituted diphenyl leukotriene B 4  (LTB 4 ) antagonists, to compositions containing such compounds, and to methods of using such compounds for treatment of inflammatory diseases.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This case claims the priority benefit of U.S. Provisional PatentApplication Serial No. 60/164,703, filed 11 Nov. 1999, the disclosure ofwhich is incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] The metabolic routes in which various compounds arebiosynthesized from arachidonic acid, are collectively called the“Arachidonic Acid Cascade.”

[0003] Leukotriene B₄ (LTB₄) is one of many products resulting from theacrachidonic acid cascade.

[0004] Moreover, LTB₄ in high concentration has been detected at thesites of various inflammatory conditions, for example, rheumatism,spinal arthritis (see Klickstein L. B., Shapleigh, C. and Goetzl, E. J.(1980) J. Clin. Invest., 66, 1166-1170), gout (Rae, S. A., Davidson, E.M. and Smith, M. J. H. (1982) Lancet II 1122-1123), psoriasis (seeGrabbe, J., Czarnetzki, B. M., Rosenbach, T. and Mardin, M. (1984) J.Invest. Dermatol., 82, 477-479), ulcerative colitis (see Sharon, P. andStenson, W. F. (1984) Gastroenterology 86, 453-460). and respiratorydisease (see O'Driscoll, B. R., Cromwell, O. and Kay, A. B. (1984) Clin.Exp., Immunol., 55, 397-404). The facts described above show that LTB₄is deeply related to various forms of inflammation. It has beensuggested that compounds antagonizing LTB₄ activity may be valuable inthe treatment of inflammatory diseases caused by tissue degradingenzymes and reactive chemicals liberated by tissue-infiltrating andaggregating polymorphonuclear leukocytes.

[0005] For example, PCT Japanese National Publication No. 6-502164describes novel monocylic or bicyclic aryl compounds are selectivelyantagonistic to LTB₄ and are useful for treatment of rheumatoidarthritis, gout, psoriasis and inflammatory bowel disease. JapaneseUnexamined Patent Publication (Kokai) No. 4-244023 describes that omega6 series unsaturated fatty acids such as γ-linolenic acid are useful fortreatment of arrhythmia, acute myocardial infarction etc, by inhibitingproduction of LTB₄. Japanese Unexamined Patent Publication No. 5-310668describes that a novel leucine derivative has an inhibitory action toLTA₄ hydrolase and is useful for treatment and prophylaxis of allergicdiseases such as bronchial asthma, various inflammatory diseases, andischemia-reperfusion disorders. Japanese Unexamined Patent Publication(Kokai) No. 1-190656 discloses that novel leukotriene B₃ dimethyl amidehas an antagonistic action to LTB₄ and is useful as anti-inflammatorydrug, anti-rheumatic drug and gout-treatment drug.

[0006] The article, “Second Generation Leukotriene B₄ ReceptorAntagonists Related to SC-41930: Heterocyclic Replacement of the MethylKetone Pharmacophore”, J. Med Chem, 1995, 38, p.858-868 by Penning,Thomas D. et. al.; describes heterocycle substituted LTB₄ antagonists.

[0007] Pyrazole LTB₄ antagonists are disclosed in the article,“Leukotriene B₄ (LTB₄) Receptor Antagonists: A Series of(Hydroxyphenyl)pyrazoles” by Richard W. Harper, et. al., J. Med Chem,1994, 37, pgs. 2411-2420.

[0008] Leukotriene B₄ antagonists, inclusive of diphenyl ethers such as2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(4-fluorophenyl)phenoxy]propoxy]phenoxy]benzoicacid, are described in U.S. Pat. No. 5,462,954, the disclosure of whichis incorporated herein by reference. The same type of leukotriene B₄antagonists are described in the article, “Synthetic andStructure/Activity Studies on Acid-Substituted 2-Arylphenols: Discoveryof2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]phenoxy]benzoicAcid, a High-Affinity Leukotriene B₄ Receptor Antagonist” by J. ScottSawyer, et. al., Journal of Medicinal Chemistry, 1995, 38, pgs.4411-4432. These diphenyl ether leukotriene B₄ antagonists, incombination with a 2′,2′-difluoronucleoside analog (e.g., GEMCITABINEHCl), have also been found to have utility in the treatment of variouscancers, as further described in Provisional Patent Application SerialNo. 60/164786, filed 11 Nov. 1999, the disclosure of which isincorporated herein by reference.

[0009] Currently, anti-inflammatory drugs are classified as steroidaland non-steroidal. Although these drugs provide anti-inflammatory actionthey all have drawbacks which limit their use. A more recent approach tothe moderation of inflammation focuses on blocking the action ofarachidonic acid metabolites.

[0010] Leukotriene B₄ antagonists are useful for a wide variety ofInflammatory Diseases, but it is expected that various of theseantagonists will show superior results with particular disease states.This is one reason it is desirable to develop new leukotriene B₄antagonists such as the compounds of this invention.

SUMMARY OF THE INVENTION

[0011] The present invention is directed to novel heterocyclesubstituted diphenyl compounds of formula (I)

[0012] Another aspect of this invention are pharmaceutical compositionscontaining the compounds of formula (I).

[0013] Another aspect of this invention is a method of using thecompounds of the invention in the prevention and treatment of LTB₄induced illnesses.

[0014] Another aspect of this invention is a compound of formula (I) foruse as a medicament in the treatment or prevention of InflammatoryDiseases.

[0015] Another aspect of this invention is a process for preparing acompound of Formula (I).

DETAILED DESCRIPTION

[0016] I. Definitions:

[0017] The term, “Acidic Group” means an organic group which whenattached as the “Z” substituent of formula (I) or the “Z2” substituentof formula (II) acts as a proton donor capable of hydrogen bonding. Anillustrative acidic group is carboxyl.

[0018] The term, “Active Ingredient” means the diphenyl leukotriene B₄antagonist compounds generically described by formula I and formula IIor the list of specific diphenyl compounds disclosed, infra., as well asthe salts, solvates, and prodrugs of such compounds.

[0019] The term, “alkenyl” means a monovalent radical of the genericformula C_(n)H_(2n) such as ethenyl, n-propenyl, isopropeneyl,n-butenyl, isobutenyl, 2-butenyl, and 3-butenyl.

[0020] The term, “alkyl” by itself or as part of another substituentmeans, unless otherwise defined, a straight or branched chain monovalenthydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl,tertiary butyl, sec-butyl, n-pentyl, and n-hexyl.

[0021] The term, “alkaryl” means an aryl radical substituted with analkyl or substituted aryl group, for example:

[0022] In the term, “C₆-C₂₀ alkaryl” the numerical subscripts refer tothe total number of carbon atoms in the radical.

[0023] The term, “C₆-C₂₀ aralkyl” means an alkyl radical substitutedwith an aryl or substituted aryl group, for example:

[0024] In the term, “C₆-C₂₀ aralkyl” the numerical subscripts refer tothe total number of carbon atoms in the radical.

[0025] The term, “carbocyclic group” refers to a five, six, seven, oreight membered saturated, unsaturated or aromatic ring containing onlycarbon and hydrogen (e.g., benzene, cyclohexene, cyclohexane,cyclopentane).

[0026] The term, “cycloalkyl” means a carbocyclic non-aromaticmonovalent radical such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl.

[0027] The term, “halo” means fluoro, chloro, bromo, or iodo.

[0028] The term, “heterocyclic radical(s)” refers to a radical having asaturated, unsaturated or aromatic five membered substituted orunsubstituted ring containing from 1 to 4 hetero atoms.

[0029] The term, “Inflammatory Diseases” refers to diseases such asinflammatory bowel disease, sepsis, septic shock, adult respiratorydistress syndrome, pancreatitis, trauma-induced shock, bronchial asthma,allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acutebronchitis, chronic bronchitis, acute bronchiolitis, chronicbronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosingspondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathricspondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis,reactive arthropathy, infectious or post-infectious arthritis,gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungalarthritis, syphilitic arthritis, Lyme disease, arthritis associated with“vasculitic syndromes”, polyarteritis nodosa, hypersensitivityvasculitis, Luegenec's granulomatosis, polymyalgin rheumatica, jointcell arteritis, calcium crystal deposition arthropathris, pseudo gout,non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tenniselbow), carpal tunnel syndrome, repetitive use injury (typing),miscellaneous forms of arthritis, neuropathic joint disease (charco andjoint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura,hypertrophic osteoarthropathy, multicentric reticulohistiocytosis,arthritis associated with certain diseases, surcoilosis,hemochromatosis, sickle cell disease and other hemoglobinopathries,hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism,acromegaly, familial Mediterranean fever, Behat's Disease, systemiclupus erythrematosis, or relapsing polychondritis and related diseaseswhich comprises administering to a mammal in need of such treatment atherapeutically effective amount of the compound of formula I in anamount sufficient to act as an antagonist for leukotriene B₄ and itsdeleterious products.

[0030] The term, “LTB₄ antagonist” means a pharmaceutical agent capableof preventing or reducing to a therapeutically significant degree theadverse activity of LTB₄ in mammals and having a average CD11b/CD18 IC₅₀(nM) assay result of 10000 or less and preferably of 100 or less.

[0031] The term, “mammal” includes human.

[0032] The term, “N-sulfonamidyl” means the radical:

[0033] where R12 is C₁-C₁₀ alkyl, aryl, C1-C6 alkyl substituted aryl,C₆-C₂₀ alkaryl, or C₆-C₂₀ aralkyl.

[0034] The term, “substituted alkyl” means an alkyl group furthersubstituted with one or more radical(s) selected from halo, C₁-C₆ alkyl,aryl, benzyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₁-C₈alkoxy, C₁-C₆ haloalkyl (e.g., —CF₃).

[0035] The term, “substituted aryl” means an aryl group furthersubstituted with one or more radical(s) selected from halo, C₁-C₆ alkyl,aryl, benzyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₁-C₈alkoxy, C₁-C₆ haloalkyl (e.g., —CF₃).

[0036] The term, “tetrazolyl” refers to an acidic group represented byeither of the formulae:

[0037] II. Compounds of the Invention:

[0038] The present invention is directed to novel heterocyclicsubstituted diphenyl compounds of formula (I)

[0039] wherein:

[0040] X is selected from the group consisting of,

[0041] (i) a five membered substituted or unsubstituted heterocyclicradical containing from 1 to 4 hetero atoms independently selected fromsulfur, nitrogen or oxygen; or

[0042] (ii) a fused bicyclic radical wherein a carbocyclic group isfused to two adjacent carbon atoms of the five membered heterocyclicradical, (i);

[0043] Y₁ is a bond or divalent linking group containing 1 to 9 atoms;

[0044] Y₂ and Y₃ are divalent linking groups independently selected from—CH₂—, —O—, and —S—;

[0045] Z is an Acidic Group;

[0046] R1 is C₁-C₁₀ alkyl, aryl, C₃-C₁₀ cycloalkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₆-C₂₀ aralkyl, C₆-C₂₀ alkaryl, C₁-C₁₀ haloalkyl, C₆-C₂₀aryloxy, or C₁-C₁₀ alkoxy;

[0047] R2 is hydrogen, halogen, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀alkyl, C₃-C₈ cycloalkyl, Acidic Group, or —(CH₂)₁₋₇(Acidic Group);

[0048] R3 is hydrogen, halogen, C₁-C₁₀ alkyl, aryl, C₁-C₁₀ haloalkyl,C₁-C₁₀ alkoxy, C₁-C₁₀ aryloxy, C₃-C₈ cycloalkyl;

[0049] R4 is C₁-C₄ alkyl, C₃-C₄ cycloalkyl, —(CH₂)₁₋₇(cycloalkyl), C₂-C₄alkenyl, C₂-C₄ alkynyl, benzyl, or aryl; and

[0050] n is 0, 1, 2, 3, 4, 5, or 6;

[0051] or a pharmaceutically acceptable salt, solvate, or prodrugderivative thereof.

[0052] III. Preferred Compounds of the Invention:

[0053] III A. Preferred X Substituents:

[0054] A “substituted heterocyclic radical” is preferably Substitutedwith from 1 to 3 groups independently selected from hydrogen, halo,C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkoxy, aryl, or C₆-C₂₀ aryloxy.

[0055] Preferred Group 1 of X Substituent (Symbol, “PG1-X”)

[0056] Preferred compounds of the invention are those wherein X is aheterocyclic radical selected from the group consisting of substituentsrepresented by the following structural formulae:

[0057] where R10 is a radical selected from hydrogen or C₁-C₄ alkyl; andR11 is a radical selected from hydrogen, halo, C₁-C₁₀ alkyl, C₁-C₁₀haloalkyl, C₁-C₁₀ alkoxy, aryl, or C₆-C₂₀ aryloxy. Preferred R10 groupsare hydrogen, methyl, or phenyl. Moreover, any of the above heterocyclicradicals illustrated by structural formulae may attach to the diphenylleukotriene antagonist of formulae (I) by any monovalent bondoriginating on a suitable carbon or nitrogen atom in its ring structure.

[0058] For example, the pyrrole radical may attach to the diphenylmolecule by a single bond originating at any carbon atom or any nitrogenatom which has less than three bonds in the hererocyclic ring;

[0059] Location of Attachment Bond for Pyrrole,

[0060] A preferred form of the substituent X is a fused bicyclic radicalwherein a carbocyclic group is fused to two adjacent carbon atoms of thefive membered heterocyclic radical, for example:

[0061] III B. Preferred Group 2 of X Substituent (Symbol, “PG2-X”):

[0062] Most preferred as the X substituents are the heterocyclicradicals;

[0063] III C. Excluded X Substituents:

[0064] The heterocyclic radical X of Formula (I) does not include3-bromo-1,2,4 thiadiazole since the LTB₄ antagonist activity ofcompounds containing this radical is considered too low to be an aspectof this invention.

[0065] III D. Preferred Y₁ Substituents:

[0066] Y₁ is a bond or divalent linking group containing 1 to 9 atomsindependently selected from carbon, hydrogen, sulfur, nitrogen, andoxygen;

[0067] Preferred Group 1 of Y₁ Substituent (Symbol, “PG1-Y₁”)

[0068] Preferred compounds of the invention are those wherein Y₁ is adivalent linking group selected from the group consisting ofsubstituents represented by the following formulae:

[0069] where R13 is hydrogen, methyl, or ethyl;

[0070] The above divalent groups may be used in their forward orreversed positions. For example, the group;

[0071] may be positioned as either,

[0072] in the displayed fragment of formula (I).

[0073] III E. Preferred Group 2 of Y₁Substituent (Symbol, “PG2-Y₁”):

[0074] The most preferred divalent Y₁ substituent is the group;

[0075] III F. Preferred Group 1 of Y₂ Substituent (Symbol, “PG1-Y₂”) andPreferred Group 1 of Y₃ substituent (symbol, “PG1-Y₃”):

[0076] The Y₂ and Y₃ substituents are preferably selected from —S— and—O—.

[0077] III G. Preferred Group 2 of Y₂ Substituent (Symbol, “PG2-Y2”) andPreferred Group 2 of Y₃ substituent (symbol, “PG2-Y₃”):

[0078] Most preferably both Y₂ and Y₃ are the group;

[0079] III H. Preferred Group 1 of Z Substituent (Symbol, “PG1-Z”):

[0080] Z is the Acidic Group as previously defined. Preferred is anacidic group selected from the following:

[0081] where R12 is C₁-C₁₀ alkyl, aryl, C₆-C₂₀ alkaryl, or C₆-C₂₀aralkyl. Preferred R12 groups are represented by the formulae:

[0082] III I. Preferred Group 2 of Z Substituent (Symbol, “PG2-Z”):

[0083] Highly preferred are the acidic groups; -5-tetrazolyl,

[0084] N-acyl sulfonamide, —SO₃H, and carboxyl.

[0085] III J. Preferred Group 3 of Z Substituent (Symbol, “PG3-Z”):

[0086] Carboxyl is the most preferred Z substituent.

[0087] III K. Preferred Group 1 of n Subscript Variable (Symbol,“PG1-n”)

[0088] The most preferred integer values for the divalent linking group,—(CH₂)_(n)—, are n=1, n=2, and n=3.

[0089] III L. Preferred Group 2 of n Subscript Variable (Symbol,“PG2-n”)

[0090] The most preferred integer value of n for the divalent linkinggroup, —(CH₂)_(n)— is n=1.

[0091] III M. Preferred Group 1 of R1 Substituent (Symbol, “PG1-R1”):

[0092] A preferred R1 group is methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, and 2-propenyl; with n-propyl being most preferred.

[0093] III N. Preferred Group 1 of R2 Substituent (Symbol, “PG1-R2”)andPreferred Group 1 of R3 Substituent (Symbol, “PG1-R3”):

[0094] Preferred R2 and R3 groups are those wherein R2 and R3 areindependently selected from hydrogen or methyl, ethyl, methoxy, ethoxy,halo, or —CF₃; with R2 and R3 both being hydrogen as most preferred.

[0095] III O. Preferred Group 1 of R4 Substituent (Symbol, “PG1-R4”:)

[0096] Preferred R4 substituents are ethyl, propyl, and isopropyl.

[0097] III P. Combinations of Substituents of the Compound of Formula(I):

[0098] The substituents of formula (I) are defined as “Z”, “X”, “n”,“R1”, “R2”, “R3”, “R4”, “Y1”, “Y2”, and “Y3”. Moreover, as described inthe preceding section, within each of the defined substituents ofFormula (I) are “preferred” and “most preferred” subgroups which definethe variety of substituents to be used in the definition of LTB₄antagonists of the invention. These preferred subgroups are defined bydesignations such as “PG1-R4” as recited above. It is often advantageousto use combinations of preferred groups or combinations of preferredgroups together with the general definition of variables given inFormula (I). Suitable combinations of substituents are shown in thefollowing three Tables (viz., R-Table, Y-Table & XZn-Table).

[0099] The following R-Table is used to select combinations of generaland preferred groupings of the variables R1, R2, R3 and R4 forsubstitution in formula (I), as follows: R-Table R variables R1 R2 R3 R4Combination group group group group Code choice choice choice choice R01R1 R2 R3 R4 R02 R1 R2 R3 PG1-R4 R03 R1 R2 PG1-R3 R4 R04 R1 R2 PG1-R3PG1-R4 R05 R1 PG1-R2 R3 R4 R06 R1 PG1-R2 R3 PG1-R4 R07 R1 PG1-R2 PG1-R3R4 R08 R1 PG1-R2 PG1-R3 PG1-R4 R09 PG1-R1 R2 R3 R4 R10 PG1-01 R2 R3PG1-R4 R11 PG1-R1 R2 PG1-R3 R4 R12 PG1-R1 R2 PG1-R3 PG1-R4 R13 PG1-R1PG1-R2 R3 R4 R14 PG1-R1 PG1-R2 R3 PG1-R4 R15 PG1-R1 PG1-R2 PG1-R3 R4 R16PG1-R1 PG1-R2 PG1-R3 PG1-R4

[0100] Thus, for example, the substituent combination, “R14” describes asubstituent combinatorial choice for Formula (I) wherein R1 is selectedfrom the preferred set of variables, “PG1-R1”, that is, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, and 2-propenyl; the R2substituent is selected from the preferred set of variables, “PG1-R2”,that is, hydrogen or methyl, ethyl, methoxy, ethoxy, halo, or —CF₃; thevariable R3 has the scope defined in the generic formula (I), and thesubstituents suitable for R4 are selected from the preferred group,“PG1-R4” having the preferred set of variables, ethyl, propyl, andisopropyl.

[0101] The following Y-Table is used to select broad and preferredgroupings of the variables Y1, Y2, and Y3 for substitution in formula(I), as follows: Y-Table Y variables combination Y1 group Y2 group Y3group code choice choice choice Y01 Y1 Y2 Y3 Y02 Y1 Y2 PG1-Y3 Y03 Y1 Y2PG2-Y3 Y04 Y1 PG1-Y2 Y3 Y05 Y1 PG2-Y2 Y3 Y06 Y1 PG1-Y2 PG1-Y3 Y07 Y1PG1-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PG1-Y3 Y09 Y1 PG2-Y2 PG2-Y3 Y10 PG1-Y1 Y2 Y3Y11 PG1-Y1 Y2 PG1-Y3 Y12 PG1-Y1 Y2 PG2-Y3 Y13 PG1-Y1 PG1-Y2 Y3 Y14PG1-Y1 PG1-Y2 PG1-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3 Y16 PG1-Y1 PG2-Y2 Y3 Y17PG1-Y1 PG2-Y2 PG1-Y3 Y18 PG1-Y1 PG2-Y2 PG2-Y3 Y19 PG2-Y1 Y2 Y3 Y20PG2-Y1 Y2 PG1-Y3 Y21 PG2-Y1 Y2 PG2-Y3 Y22 PG2-Y1 PG1-Y2 Y3 Y23 PG2-Y1PG1-Y2 PG1-Y3 Y24 PG2-Y1 PG1-Y2 PG2-Y3 Y25 PG2-Y1 PG2-Y2 Y3 Y26 PG2-Y1PG2-Y2 PG1-Y3 Y27 PG2-Y1 PG2-Y2 PG2-Y3

[0102] The following XZn-Table is used to select broad and preferredgroupings of the variables X, Z, and n for substitution in formula (I),as follows: XZn-Table XZn variables X Z n integer combination groupGroup group code choice Choice choice XZn01 X Z n XZn02 X Z PG1-n XZn03X Z PG2-n XZn04 X PG1-Z n XZn05 X PG2-Z n XZn06 X PG3-Z n XZn07 X PG1-ZPG1-n XZn08 X PG2-Z PG1-n XZn09 X PG3-Z PG1-n XZn10 X PG1-Z PG2-n XZn11X PG2-Z PG2-n XZn12 X PG3-Z PG2-n XZn13 PG1-X Z n XZn14 PG1-X Z PG1-nXZn15 PG1-X Z PG2-n XZn16 PG1-X PG1-Z n XZn17 PG1-X PG2-Z n XZn18 PG1-XPG3-Z n XZn19 PG2-X PG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn21 PG2-XPG3-Z PG1-n XZn22 PG2-X PG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n XZn24 PG2-XPG3-Z PG2-n

[0103] How to Use the Tables:

[0104] Any of the individual 16 combinations of the R substituentsdepicted in the R-Table may be used in combination with any of the 27individual combinations of Y substituents depicted in the Y-Table, whichmay be used with any of the 24 combinations of XZn substituents depictedin the XZn-Table. For example, the substituent combination choice “R07,Y21, XZn03” defines substituent set selections for a subset of formula(I) useful in the practice of the invention.

[0105] III Q. Preferred Compounds of the Invention are Described byFormula (II):

[0106] wherein;

[0107] X2 is a heterocyclic radical selected from,

[0108] R21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl, iso-propyl,n-butyl, sec-butyl, or tert-butyl; and

[0109] R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro, —CF₃, ortert-butyl.

[0110] Z2 is carboxyl, tetrazolyl, N-sulfonamidyl.

[0111] Preferred Compounds of the Invention:

[0112] III R. Specific Compounds Preferred as LTB₄ Antagonists areRepresented by the Following Structural Formulae:

[0113] and all acid, salt, solvate and prodrug derivatives thereof.

[0114] III S. Highly Preferred Compounds of the Invention are asFollows:

[0115] and all acid, salt, solvate and prodrug derivatives thereof.

[0116] The salts of the above diphenyl LTB₄ antagonists of theinvention, represented by formulae (I) and (II) and the specificcompounds set out by structural formulae in sections IIIR and IIISherein, are an additional aspect of the invention. The compounds of theinvention possess an Acidic Group(s) and at these sites various saltsmay be formed which are more water soluble and/or physiologicallysuitable than the parent compound in its acid form. Representativepharmaceutically acceptable salts, include but are not limited to, thealkali and alkaline earth salts such as lithium, sodium, potassium,calcium, magnesium, aluminum and the like. Sodium salts are particularlypreferred. Salts are conveniently prepared from the free acid bytreating the acid form in solution with a base or by exposing the acidto an ion exchange resin. For example, the (Acidic Group) of the Z ofFormula (I) may be selected as —CO₂H and salts may be formed by reactionwith appropriate bases (e.g., NaOH, KOH) to yield the correspondingsodium or potassium salt.

[0117] Included within the definition of pharmaceutically acceptablesalts are the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention, for example, ammonium,quaternary ammonium, and amine cations, derived from nitrogenous basesof sufficient basicity to form salts with the LTB₄ antagonist compoundsof this invention (see, for example, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Phar. Sci., 66: 1-19 (1977)).

[0118] Certain compounds of the invention may possess one or more chiralcenters and may thus exist in optically active forms. All suchstereoisomers as well as the mixtures thereof are intended to beincluded in the invention. If a particular stereoisomer is desired, itcan be prepared by methods well known in the art, for example, by usingstereospecific reactions with starting materials which contain theasymmetric centers and are already resolved or, alternatively, bymethods which lead to mixtures of the stereoisomers and subsequentresolution by known methods. For example, a racemic mixture may bereacted with a single enantiomer of some other compound. This changesthe racemic form into a mixture of diastereomers. Then, because thediastereomers have different melting points, different boiling points,and different solubilities, they can be separated by conventional means,such as crystallization.

[0119] Prodrugs are derivatives of the compounds of Formula (I) and(II), supra., which have chemically or metabolically cleavable groupsand become by solvolysis or under physiological conditions the compoundsof the invention which are pharmaceutically active in vivo. Derivativesof the compounds of this invention have activity in both their acid andbase derivative forms, but the acid derivative form often offersadvantages of solubility, tissue compatibility, or delayed release in amammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9,21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives wellknown to practitioners of the art, such as, for example, esters preparedby reaction of the parent acidic compound with a suitable alcohol, oramides prepared by reaction of the parent acid compound with a suitableamine. Simple aliphatic or aromatic esters derived from acidic groupspendent on the compounds of this invention are preferred prodrugs. Insome cases it is desirable to prepare double ester type prodrugs such as(acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.Particularly preferred esters as prodrugs are methyl, ethyl, propyl,isopropyl, n-butyl; isobutyl, tert-butyl, morpholinoethyl, andN,N-diethylglycolamido.

[0120] Esters of carboxylic acids are preferred prodrugs of thecompounds of the invention (viz., the compounds of Formula I, Formula IIand the specific compounds set out in Section IIIR and IIIS, herein).

[0121] Methyl ester prodrugs may be prepared by reaction of the acidform of a compound of formula (I) in a medium such as methanol with anacid or base esterification catalyst (e.g., NaOH, H₂SO₄). Ethyl esterprodrugs are prepared in similar fashion using ethanol in place ofmethanol.

[0122] N,N-diethylglycolamido ester prodrugs may be prepared by reactionof the sodium salt of a compound of Formula (I) (in a medium such asdimethylformamide) with 2-chloro-N,N-diethylacetamide (available fromAldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).

[0123] Morpholinylethyl ester prodrugs may be prepared by reaction ofthe sodium salt of a compound of Formula (I) (in a medium such asdimethylformamide) 4-(2-chloroethyl)morpholine hydrochloride (availablefrom Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).

[0124] Preferred compounds of the invention are compounds of Formula(I), or Formula (II) or the specific compounds of sections IIIR and IIISshown above by structural formula; wherein the acid, salt and prodrugderivatives thereof are respectively selected from: carboxylic acid,sodium salt, and ester prodrug.

[0125] IV. Method of Making the Compounds of the Invention

[0126] General reaction schemes (not represented to be specificExamples) applicable for synthesis of the LTB₄ antagonist compoundsrepresented by formula (I) are set out below. Numerous literaturereferences and Chemical Abstract registry numbers (e.g., RN 152609-60-4)are supplied as additional aids for preparing reagents used inpracticing the synthesis schemes of the invention.

Reaction Schemes for Making the Compounds of the Invention

[0127] The following scheme illustrates a process for making Example(1), a 4-substituted oxazole LTB₄ receptor antagonist:

[0128] Known chloride (26) may be alkylated with benzyl bromide toprovide chloride (28). Reaction with known ester (30), catalyzed by asuitable base, provides acetophenone (32). Oxidation withbis(trifluoroacetoxy)iodobenzene gives alpha-hydroxy ketone (34), thatmay be cyclized with triflic anhydride and formamide to give the4-substituted oxazole (36). Debenzylation with boron trifluorideetherate and ethanethiol gives oxazole (38), that is hydrolyzed andprotonated to provide Example (1).

Scheme 2

[0129] The following scheme illustrates a process for making Example(2), a 5(4)-substituted imidazole LTB₄ receptor antagonist:

[0130] The trimethylsilyl enol ether of acetophenone (32) is formed andtreated with N-chlorosuccinimide followed by tetra-n-butylammoniumfluoride to provide the chloroketone (40). Treatment of (40) with2-benzyl-2-thiopseudourea and base provides imidazole (42), that istreated with boron trifluoride etherate and ethanethiol to giveimidazole (44). Hydrolysis and protonation provide Example (2) as thehydrochloride salt.

Scheme 3

[0131] The following scheme illustrates a process for making Example(3), a 4-substituted thiazole LTB₄ receptor antagonist:

[0132] Chloroketone (40) is treated with thioformamide and magnesiumcarbonate to give thiazole (46), that is debenzylated with borontrifluoride etherate and ethanethiol giving thiazole (48). Hydrolysisand protonation provides Example (3).

Scheme 4

[0133] The following scheme illustrates a process for making Example(4), a 5(3)-substituted pyrazole LTB₄ receptor antagonist:

[0134] Treatment of acetophenone (32) with N,N-dimethylformamidedimethyl acetal gives enone (50), that may be hydrolyzed, protonated,and then heated with hydrazine hydrate to provide pyrazole (52).Debenzylation of the resulting pyrazole with boron trifluoride etherateand ethanethiol gives Example (4).

Scheme 5

[0135] The following scheme illustrates a process for making Example(5), a 5-substituted isoxazole LTB₄ receptor antagonist:

[0136] Treatment of enone (50) with hydroxylamine provides isoxazole(54), that is debenzylated with boron trifluoride etherate andethanethiol to give isoxazole (56). Hydrolysis and protonation providesExample (5).

Scheme 6

[0137] The following scheme illustrates a process for making Example(6), a 5(4)-substituted 1,2,3-triazole LTB₄ receptor antagonist:

[0138] Known phenol (30) is alkylated with known chloride (58) to givearyl bromide (60). Treatment of (60) with tri-n-butylethynyltin and apalladium catalyst gives alkyne (62). Heating (62) with trimethylsilylazide provides triazole (64), that is debenzylated with borontrifluoride etherate and ethanethiol to give triazole (66). Hydrolysisand protonation provides Example (6).

Scheme 7

[0139] The following scheme illustrates a process for making Example(7), a 1-substituted pyrrole LTB₄ receptor antagonist:

[0140] References for formation of 1-aryl substituted pyrroles: M. Mureand J. P. Klinman, J. Am. Chem. Soc. 1995, 117(34), 8698; Y. Lee et al.J. Am. Chem. Soc. 1996, 118(30), 7241

[0141] 4-Ethylbenzene-1,3-diol (68) is treated with potassiumnitrosodisulfonate followed by 3-pyrroline and benzylbromide and a baseto provide pyrrole (70). Alkylation with 1-bromo-3-chloropropane giveschloride (72), that is used to alkylate phenol (30) to give pyrrole(74). Debenzylation with boron trifluoride etherate and ethanethiolprovides Example (7).

Scheme 8

[0142] The following scheme illustrates a process for making Example(8), a 5-substituted 1,2,4-thiadiazole LTB₄ receptor antagonist:

[0143] The palladium-catalyzed addition of4,4,5,5-tetramethyl-[1,3,2]dioxaborolane to bromide (60) gives boronicester (76). The palladium-catalyzed addition of3-bromo-5-chloro-1,2,4-thiadiazole to (76) gives ester (78).Debenzylation with boron trifluoride etherate and ethanethiol, followedby hydrolysis and protonation, gives Example (8).

Scheme 9

[0144] The following scheme illustrates a process for making Example(9), a 2-substituted thiophene LTB₄ receptor antagonist:

[0145] The palladium-catalyzed addition of boronic ester (76) to2-bromothiophene, followed by debenzylation with boron trifluorideetherate and ethanethiol, provides thiophene (80). Hydrolysis and saltformation provides Example (9).

Scheme 10

[0146] The following scheme illustrates a process for making Example(10), a 4-substituted pyrazole LTB₄ receptor antagonist:

[0147] The palladium-catalyzed addition of boronic ester (76) to1-methyl-4-iodopyrazole provides pyrazole (82). Debenzylation with borontrifluoride etherate and ethanethiol, followed by hydrolysis andprotonation, provides Example (10).

Scheme 11

[0148] The following scheme illustrates a process for making Example(11), a 2-substituted thiazole LTB₄ receptor antagonist:

[0149] The palladium-catalyzed addition of boronic ester (76) to2-bromothizaole provides thiazole (84). Debenzylation with borontrifluoride etherate and ethanethiol gives thiazole (86). Hydrolysis andprotonation provides Example (11).

Scheme 12

[0150] The following scheme illustrates a process for making Example(12), a 4-substituted isoxazole LTB₄ receptor antagonist:

[0151] The palladium-catalyzed addition of boronic ester (76) to3,5-dimethyl-4-iodoisoxazole provides oxazole (88). Debenzylation withtrimethylsilyl iodide, followed by hydrolysis and salt formation,provides Example (12).

Scheme 13

[0152] The following scheme illustrates a process for making Example(13), a 2-substituted furan LTB₄ receptor antagonist:

[0153] Debenzylation of bromide (60) with boron tribromide providesphenol (90), that is treated with tert-butyldimethylsilyl chloride andimidazole to give silyl ether (92). The palladium-catalyzed addition of(92) to furan-2-boronic acid provides furan (94). Hydrolysis and saltformation gives Example (13).

Scheme 14

[0154] The following scheme illustrates a process for making Example(14), a 3-substituted furan LTB₄ receptor antagonist:

[0155] The palladium-catalyzed addition of (92) to furan-3-boronic acidprovides furan (96). Hydrolysis and salt formation gives Example (14).

Scheme 15

[0156] The following scheme illustrates a process for making Example(15), a 3-substituted tetrahydrofuran LTB₄ receptor antagonist:

[0157] The palladium-catalyzed addition of bromide (60) tofuran-3-boronic acid provides furan (98). Hydrogenation over a palladiumcatalyst gives tetrahydrofuran (100). Hydrolysis and salt formationgives Example (15).

Scheme 16

[0158] The following scheme illustrates a process for making Example(16), a 2-substituted pyrrolidine LTB₄ receptor antagonist:

[0159] The palladium-catalyzed addition of bromide (60) to N-bocpyrrole-2-boronic acid provides pyrrole (102). Hydrogenation over apalladium catalyst gives pyrrolidine (104). Hydrolysis and saltformation gives pyrrolidine (106). Treatment with hydrochloric acidprovides Example (16) as the hydrochloride salt.

Scheme 17

[0160] The following scheme illustrates a process for making Example(17), a 3-substituted thiophene LTB₄ receptor antagonist:

[0161] The palladium-catalyzed addition of bromide (58) tothiophene-3-boronic acid provides thiophene (108). Alkylation of knownphenol (110) with (108) catalyzed by base provides thiophene (112).Debenzylation with boron tribromide gives thiophene (114). Hydrolysisand protonation provide Example (17).

Scheme 18

[0162] The following scheme illustrates a process for making Example(18), a 5-substituted 1,2,3,4-thiatriazole LTB₄ receptor antagonist:

[0163] Phenol (30) is alkylated with 1-bromo-3-chloropropane to givechloride (116), that is in turn to be treated with known aldehyde (118)and a base, followed by benzylation with benzyl bromide and a base, toprovide aldehyde (120). From aldehyde (120) is made the thioacetal bytreatment with 1,2-ethanedithiol. The resulting thioacetal is then to betreated with base to provide the thioacid. Treatment with piperidinemakes piperidinium salt (122). By the teaching of Ikeda, infra, (thedisclosure of which is incorporated herein by reference) treatment of(122) with 2-chloropyridinium methyl iodide followed by azide ion willgive the 1,2,3,4-thiatriazole (124). Debenzylation with borontrifluoride etherate and ethanethiol, followed by hydrolysis andprotonation, will provide the product of Example (18).

Scheme 19

[0164] The following scheme illustrates a process for making Example(19), a 4-substituted 1,2,3-thiadiazole LTB₄ receptor antagonist:

[0165] Treatment of acetophenone (32) with ethyl carbazate will give thehydrazone (128). Use of thionyl chloride by the method of Thomas et. al.(infra., the disclosure of which is incorporated herein by reference)will give an intermediate 1,2,3-thiadiazole (130), that is to bedebenzylated with boron trifluoride etherate and ethanethiol, thenhydrolyzed and protonated to give the product of Example (19).

Scheme 20

[0166] The following scheme illustrates a process for making Example(20), a 3-substituted 1,2,5-thiadiazole LTB₄ receptor antagonist:

[0167] Alkyne (62) is to be treated with trithiazyl trichloride by themethod of Thomas et. al. (infra., the disclosure of which isincorporated herein by reference) to provide thiadiazole (132).Debenzylation with boron trifluoride etherate and ethanethiol, followedby hydrolysis and protonation, will provide the product of Example (20).

Scheme 21

[0168] The following scheme illustrates a process for making Example(21), a 2-substituted 1,3,4-thiadiazole LTB₄ receptor antagonist:

[0169] The palladium-catalyzed addition of boronic ester (76) to2-bromo-1,3,4-thiadiazole will provide ester (134). Debenzylation withboron trifluoride etherate and ethanethiol, followed by hydrolysis andprotonation, will provide the product of Example (21).

Scheme 22

[0170] The following scheme illustrates a process for making Example(22), a 5-substituted isothiazole LTB₄ receptor antagonist:

[0171] The palladium-catalyzed addition of bromide (58) to3-methylisothiazole-5-boronic acid will provide isothiazole (136).Alkylation of phenol (30) with (136) catalyzed by base will provideisothiazole (138). Debenzylation with boron trifluoride etherate andethanethiol, followed by hydrolysis and protonation, will provide theproduct of Example (22).

Scheme 23

[0172] The following scheme illustrates a process for making Example(23), a 2-substituted oxazole LTB₄ receptor antagonist:

[0173] The palladium-catalyzed addition of boronic ester (76) to2-bromooxazole will provide oxazole (140). Debenzylation with borontrifluoride etherate and ethanethiol, followed by hydrolysis andprotonation, will provide the product of Example (23).

Scheme 24

[0174] The following scheme illustrates a process for making Example(24), a 3-substituted thiophane LTB₄ receptor antagonist:

[0175] Thiophene (114) may be reduced in the presence of triethylsilaneand trifluoroacetic acid by the method of Kursanov et. al. (infra., thedisclosure of which is incorporated herein by reference) to provide thethiophane (142). Hydrolysis and protonation will provide the product ofExample (24).

V. PREPARATIVE EXAMPLES 1 TO 17 Example 1 Preparation of2-{3-[3-(2-Ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoicacid

[0176]

[0177] known compound: RN# 156005-61-7

[0178] R. W. Harper et al., J. Med. Chem. 1994, 37(15), 2411-20

[0179] A. Preparation of1-[2-benzyloxy-4-(3-chloropropoxy)-5-ethylphenyl]ethanone.

[0180] A mixture of1-[2-hydroxy-4-(3-chloropropoxy)-5-ethylphenyl]ethanone (26.1 g, 102mmol), cesium carbonate (33.4 g, 103 mmol), and benzyl bromide (12.2 ml,103 mmol), in N,N-dimethylformamide (300 mL) was stirred for 5 h at roomtemperature. The mixture was diluted with ethyl acetate and washed fourtimes with water. The organic layer was dried (sodium sulfate),filtered, and concentrated in vacuo. The resulting oil was trituratedwith ethyl acetate and hexane, allowed to stand for 18 h, then cooled at0° C. for 3 h. The resulting precipitate was collected via vacuumfiltration to provide 24.3 g (69%) of the title compound as whitecrystals: mp 60-61° C. ¹H NMR (CDCl₃) δ 7.68 (s, 1H), 7.40 (m, 5H), 6.48(s, 1H), 5.17 (s, 2H), 4.13 (t, J=6 Hz, 2H), 3.75 (t, J=6 Hz, 2H), 2.56(s, 3H), 2.55 (q, J=7 Hz, 2H), 2.26 (quintet, J=6 Hz, 2H), 1.16 (t, J=7Hz, 3H); TOF MS ES⁺ exact mass calculated for C₂₀H₂₄ClO₃ (p+1): m/z347.1414. Found: 347.1402; IR (CHCl₃, cm⁻¹) 1659, 1602, 1266.

[0181] Anal. Calcd for C₂₀H₂₃ClO₃: C, 69.26; H, 6.68. Found: C, 69.30;H, 6.52.

[0182] B. Preparation of2-{3-[3-(4-acetyl-5-benzyloxy-2-ethylphenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester.

[0183] A mixture of1-[2-benzyloxy-4-(3-chloropropoxy)-5-ethylphenyl]ethanone (7.27 g, 21.0mmol) and sodium iodide (3.14 g, 23.1 mmol) in 2-butanone (100 mL) washeated at reflux for 18 h. The mixture was cooled to room temperature,filtered, and concentrated in vacuo. The residue was dissolved inN,N-dimethylformamide (100 mL) and treated with2-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester (6.0 g, 21 mmol)and potassium carbonate (3.2 g, 23 mmol) at room temperature for 15 h.The mixture was diluted with ethyl acetate and washed four times withwater and once with saturated sodium chloride solution. The organiclayer was dried (sodium sulfate), filtered, and concentrated in vacuo.Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residueprovided 9.2 g (72%) of the title compound as a colorless oil. ¹H NMR(CDCl₃) δ 7.88 (d, J=9 Hz, 1H), 7.69 (s, 1H), 7.38 (m, 6H), 7.12 (d, J=8Hz, 1H), 7.07 (d, J=8 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.67 (d, J=8 Hz,1H), 6.50 (s, 1H), 6.44 (d, J=9 Hz, 1H), 5.14 (s, 2H), 4.20 (m, 4H),3.83 (s, 3H), 2.65 (t, J=7 Hz, 2H), 2.57 (q, J=7 Hz, 2H), 2.56 (s, 3H),2.32 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=7 Hz, 2H), 1.15 (t, J=8 Hz,3H), 0.90 (t, J=7 Hz, 3H); IR (CHCl₃, cm⁻¹) 2965, 1726, 1602, 1461.

[0184] Anal. Calcd for C₃₇H₄₀O₇: C, 74.48; H, 6.76. Found: C, 74.39; H,6.77.

[0185] C. Preparation of2-(3-{3-[5-benzyloxy-2-ethyl-4-(2-hydroxyacetyl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0186] A mixture of2-{3-[3-(4-acetyl-5-benzyloxy-2-ethylphenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester (5.31 g, 8.89 mmol) and water (10 mL) in acetonitrile(50 mL) was treated with trifluoroacetic acid (1.4 mL), 18 mmol) and[bis(trifluoroacetoxy)iodo]benzene (7.65 g, 17.8 mmol). The resultingmixture was heated at reflux for 4 h then concentrated in vacuo. Theresidue was dissolved in methylene chloride and washed once with water.The aqueous layer was extracted twice with fresh portions of methylenechloride. The combined organic layers were washed three times withsaturated sodium bicarbonate solution, once with saturated sodiumchloride solution, dried (sodium sulfate), filtered, and concentrated invacuo. Chromatography (silica gel, 20% ethyl acetate/80% hexane) of theresidue provided 1.68 g (31%) of the title compound as a brown oil. ¹HNMR (CDCl₃) δ 7.92 (s, 1H), 7.88 (d, J=9 Hz, 1H), 7.40 (m, 6H), 7.12 (d,J=9 Hz, 1H), 7.05 (d, J=9 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 6.66 (d, J=8Hz, 1H), 6.50 (s, 1H), 6.43 (d, J=8 Hz, 1H), 5.15 (s, 2H), 4.65 (s, 2H),4.22 (m, 4H), 3.83 (s, 3H), 2.65 (m, 4H), 2.34 (quintet, J=6 Hz, 2H),1.55 (hextet, J=7 Hz, 2H), 1.17 (t, J=8 Hz, 3H), 0.89 (t, J=8 Hz, 3H);TOS MS ES⁺ exact mass calculated for C₃₇H₄₁O₈ (p+1): m/z=613.2801.Found: 613.2833.

[0187] D. Preparation of2-{3-[3-(5-benzyloxy-2-ethyl-4-oxazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0188] To a solution of2-(3-{3-[5-benzyloxy-2-ethyl-4-(2-hydroxyacetyl)phenoxy]propoxy)-2-propylphenoxy)benzoicacid methyl ester (1.39 g, 2.27 mmol) in methylene chloride (20 mL)cooled to −78° C. was added triflic anhydride (0.57 mL, 3.4 mmol) and2,6-lutidine (0.40 mL, 3.4 mmol). The resulting mixture was stirred for1 h then poured into ether and water. The organic layer was separatedand washed once with saturated sodium chloride solution, dried (sodiumsulfate), filtered, and concentrated in vacuo. The residue was dissolvedin a 2:1 mixture of formamide/N,N-dimethylformamide (9 mL) and heated at120° C. in a sealed tube for 4 h. The mixture was cooled to roomtemperature and diluted with ethyl acetate. The mixture was washed fourtimes with water, once with saturated sodium chloride solution, dried(sodium sulfate), filtered, and concentrated in vacuo. Chromatography(silica gel, 10% ethyl acetate/90% hexane) of the residue provided 89 mg(6%) of the title product as a colorless oil. ¹H NMR (CDCl₃) δ 7.92 (s,1H), 7.85 (s, 1H), 7.83 (m, 2H), 7.35 (m, 6H), 7.03 (d, J=8 Hz, 1H),7.00 (d, J=8 Hz, 1H), 6.73 (d, J=8 Hz, 1H), 6.62 (d, J=8 Hz, 1H), 6.52(s, 1H), 6.35 (d, J=8 Hz, 1H), 5.07 (s, 2H), 4.14 (m, 4H), 3.76 (s, 3H),2.61 (m, 4H), 2.26 (quintet, J=6 Hz, 2H), 1.48 (hextet, J=7 Hz, 2H),1.15 (t, J=8 Hz, 3H), 0.84 (t, J=8 Hz, 3H).

[0189] E. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0190] To a solution of2-{3-[3-(5-benzyloxy-2-ethyl-4-oxazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (89 mg, 0.14 mmol) in ethanethiol (2 mL) was treatedwith boron trifluoride etherate (0.27 mL, 2.2 mmol) at room temperaturefor 4 h. The solution was poured into ether and washed once with water,once with saturated sodium bicarbonate solution, once with saturatedsodium chloride solution, dried (sodium sulfate), filtered, andconcentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85%hexane) of the residue provided 34 mg (45%) of the title product as alight brown oil. ¹H NMR (CDCl₃) δ 7.99 (d, J=1 Hz, 1H), 7.90 (d, J=1 Hz,1H), 7.88 (dd, J=8, 2 Hz, 1H), 7.38 (t, J=7 Hz, 1H), 7.15 (s, 1H), 7.10(d, J=9 Hz, 1H), 7.06 (d, J=9 Hz, 1H), 6.81 (d, J=9 Hz, 1H), 6.70 (d,J=9 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J=9 Hz, 1H), 4.20 (m, 4H), 3.83 (s,3H), 2.65 (t, J=8 Hz, 2H), 2.58 (q, J=8 Hz, 2H), 2.33 (quintet, J=6 Hz,2H), 1.55 (hextet, J=7 Hz, 2H), 1.17 (t, J=8 Hz, 3H), 0.91 (t, J=8 Hz,3H); MS ES+ m/e=532 (p+1).

[0191] F. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid.

[0192] To a solution of2-{3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (89 mg, 0.14 mmol) in methanol (2 mL) was added 1 Mlithium hydroxide solution (0.28 mL) and the resulting mixture warmed at60° C. for 3.5 h. The mixture was cooled to room temperature andconcentrated in vacuo. The aqueous residue was diluted with water andthe pH adjusted to ˜4. The mixture was extracted three times withmethylene chloride. The combined organic extracts were dried (sodiumsulfate), filtered, and concentrated in vacuo to provide 27 mg (92%) ofthe title compound as a yellow solid. ¹H NMR (DMSO-d₆) δ 12.83 (bs, 1H),10.12 (bs, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 7.78 (dd, J=8, 1 Hz, 1H),7.64 (s, 1H), 7.47 (t, J=8 Hz, 1H), 7.16 (m, 2H), 6.80 (t, J=8 Hz, 2H),6.56 (s, 1H), 6.35 (d, J=8 Hz, 1H), 4.20 (t, J=6 Hz, 2H), 4.12 (t, J=6Hz, 2H); 2.54 (m, 4H), 2.24 (quintet, J=6 Hz, 2H), 1.43 (hextet, J=8 Hz,2H), 1.10 (t, J=8 Hz, 3H), 0.80 (t, J=8 Hz, 3H); TOF MS ES⁺ exact masscalculated for C₃₀H₃₂N₇ (p+1): m/z=518.2179. Found: 518.2206; IR (KBr,cm⁻¹) 2961, 1696, 1460, 1222.

[0193] Anal. Calcd for C₃₀H₃₁NO₇: C, 69.62; H, 6.04; N, 2.71. Found: C,68.71; H, 5.82; N, 2.65.

Example 2 Preparation of2-(3-{3-[2-Ethyl-5-hydroxy-4-(3H-imidazol-4-yl)phenoxy]propoxy}-2-propyl-phenoxy)benzoicacid hydrochloride

[0194]

[0195] A. Preparation of2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0196] To a solution of2-{3-[3-(4-acetyl-5-benzyloxy-2-ethylphenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester (3.04 g, 5.09 mmol) in tetrahydrofuran (50 mL) cooledto −78° C. was added a solution of 1 M lithium hexamethyldisilazide intetrahydrofuran (11.2 mL, 11.2 mmol) portion wise. After stirring for 20min, trimethylsilyl chloride (2.6 mL, 20 mmol) was added and the mixturewarmed to 0° C. and stirred for 30 min. The mixture was evaporated invacuo and the residue dissolved in hexane. The resulting solution wasfiltered and concentrated in vacuo. The residue was dissolved intetrahydrofuran (50 mL), cooled to 0° C., and treated withN-chlorosuccinimide (750 mg, 5.6 mmol). The mixture was warmed to roomtemperature and stirred for 30 min, then heated at reflux for 2 h. Themixture was cooled to room temperature and treated with water (4 mL) anda solution of 1 N tetra-n-butylammonium fluoride in tetrahydrofuran (6mL). After stirring for 15 min the mixture was diluted in ether andwashed once with water, once with saturated sodium chloride solution,dried (sodium sulfate), filtered, and concentrated in vacuo.Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residueprovided 1.94 g (60%) of the title compound as a white solid. ¹H NMR(CDCl₃) δ 7.89 (d, J=8 Hz, 1H), 7.77 (s, 1H), 7.40 (m, 6H), 7.12 (d, J=9Hz, 1H), 7.06 (d, J=8 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.66 (d, J=8 Hz,1H), 6.49 (s, 1H), 6.43 (d, J=8 Hz, 1H), 5.15 (s, 2H), 4.68 (s, 2H),4.20 (q, J=6 Hz, 4H), 3.82 (s, 3H), 2.65 (t, J=7 Hz, 2H), 2.59 (q, J=7Hz, 2H), 2.32 (quintet, J=6 Hz, 2H), 1.54 (hextet, J=8 Hz, 2H), 1.16 (t,J=8 Hz, 3H), 0.89 (t, J=7 Hz, 3H); TOF MS ES⁺ exact mass calculated forC₃₇H₄₀ClO₇ (p+1): m/z=631.2463. Found: 631.2470; IR (CHCl₃, cm⁻¹) 2964,1720, 1603, 1461.

[0197] Anal. Calcd for C₃₇H₃₉ClO₇: C, 70.41; H, 6.23. Found: C, 70.04;H, 5.97.

[0198] B. Preparation of2-(3-{3-[5-benzyloxy-4-(2-benzylsulfanyl-3H-imidazol-4-yl)-2-ethyl-phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0199] A mixture-of2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (800 mg, 1.27 mmol), 2-benzyl-2-thiopseudoureahydrochloride (313 mg, 1.52 mmol), sodium iodide (77 mg, 0.51 mmol), andpotassium carbonate (700 mg, 5.06 mmol) in N,N-dimethylformamide (20 mL)was treated at 80° C. for 6 h. The mixture was cooled, diluted withdiethyl ether, and washed once with water. The organic layer was dried(sodium sulfate), filtered, and concentrated in vacuo. Chromatography(silica gel, 30% ethyl acetate/70% hexane) of the residue provided 376mg (40%) of the title compound as a yellow amorphous solid. ¹H NMR(CDCl₃) δ 7.89 (d, J=8 Hz, 1H), 7.36 (m, 9H), 7.20 (m, 5H), 7.21 (d, J=9Hz, 1H), 7.06 (d, J=8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 6.67 (d, J=8 Hz,1H), 6.55 (s, 1H), 6.43 (d, J=8 Hz, 1H), 5.07 (s, 2H), 4.21 (t, J=6 Hz,2H), 4.18 (t, J=6 Hz, 2H), 4.10 (s, 2H), 3.83 (S, 3H), 2.63 (m, 4H),2.31 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=7 Hz, 2H), 1.18 (t, J=8 Hz,3H), 0.90 (t, J=7 Hz, 3H); TOF MS ES⁺ exact mass calculated forC₄₅H₄₇N₂O₆S (p+1): m/z=743.3155. Found: 743.3142; IR (CHCl₃, cm⁻¹) 2963,1720, 1602, 1453.

[0200] Anal. Calcd for C₄₅H₄₆N₂O₆S: C, 72.75; H, 6.24; N, 3.77. Found:C, 72.69; H, 6.17; N, 3.56.

[0201] C. Preparation of2-(3-{3-[4-(2-benzylsulfanyl-3H-imidazol-4-yl)-2-ethyl-5-hydroxyphenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0202] A solution of2-(3-{3-[5-benzyloxy-4-(2-benzylsulfanyl-3H-imidazol-4-yl)-2-ethyl-phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (360 mg, 0.49 mmol) in ethanethiol (7 mL) was treatedwith boron trifluoride etherate at room temperature for 3.5 h. Themixture was diluted with diethyl ether and water. The organic layer wasseparated and washed with saturated sodium bicarbonate solution, dried(sodium sulfate), filtered, and concentrated in vacuo. Chromatography(silica gel, 20% ethyl acetate/80% hexane) of the residue provided 154mg (48%) of the title compound as an orange oil. ¹H NMR (CDCl₃) δ 7.85(d, J=8 Hz, 1H), 7.36 (t, J=7 Hz, 1H), 7.20 (m, 7H), 7.12 (s, 1H), 7.05(m, 3H), 6.79 (d, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 6.54 (s, 1H), 6.41(d, J=8 Hz, 1H), 4.20 (s, 2H), 4.17 (m, 4H), 3.82 (s, 3H), 2.62 (t, J=8Hz, 2H), 2.54 (q, J=7 Hz, 2H), 2.30 (quintet, J=6 Hz, 2H), 1.53 (hextet,J=8 Hz, 2H), 1.14 (t, J=7 Hz, 3H), 0.89 (t, J=8 Hz, 3H); TOF MS ES⁺exact mass calculated for C₃₈H₄₁N₂O₆S (p+1): m/z=653.2685. Found:653.2669.

[0203] Anal. Calcd for C₃₈H₄₀N₂O₆S: C, 69.92; H, 6.18; N, 4.29. Found:C, 69.44; H, 6.25; N, 3.99.

[0204] D. Preparation of2-(3-{3-[2-ethyl-5-hydroxy-4-(3H-imidazol-4-yl)phenoxy]propoxy}-2-propyl-phenoxy)benzoicacid hydrochloride.

[0205] A solution of2-(3-{3-[4-(2-benzylsulfanyl-3H-imidazol-4-yl)-2-ethyl-5-hydroxyphenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (154 mg, 0.235 mmol) in methanol (3 mL) was treatedwith 1 N lithium hydroxide solution at 60° C. for 3.5 h. The mixture wascooled to room temperature and concentrated in vacuo. The solution wasdiluted with water and adjusted to pH 4. The aqueous solution wasextracted three times with methylene chloride. The combined organiclayers were dried (sodium sulfate), filtered, and concentrated in vacuo.The residue was dissolved in ethanol (3 mL) and treated with 0.2 Nsodium hydroxide solution (1 mL) and Raney nickel (75 mg) at 75° C. for4 h. The mixture was cooled to room temperature, filtered throughCelite™, and the filtrate concentrated in vacuo. The residue was dilutedwith water and adjusted to pH 2 with 1 N hydrochloric acid. Theresulting precipitate was collected via vacuum filtration to provide 27mg (21%) of the title compound. TOF MS ES⁺ exact mass calculated forC₃₀H₃₃N₂O₆ (p+1): m/z=517.2339. Found: 517.2340.

Example 3 Preparation of2-{3-[3-(2-Ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoicacid

[0206]

[0207] A. Preparation of2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0208] A mixture of2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (500 mg, 0.792 mmol), thioformamide (20 mL, 8.0 mmol),and magnesium carbonate in dioxane (10 mL) was heated at reflux for 2 h.The mixture was cooled to room temperature and diluted with diethylether and 0.2 M sodium hydroxide solution. The organic layer wasseparated, washed with saturated sodium chloride solution, dried (sodiumsulfate), filtered, and concentrated in vacuo. Chromatography (silicagel, 10% ethyl acetate/90% hexane) of the residue provided 254 mg (50%)of the title compound as a colorless oil. ¹H NMR (CDCl₃) δ 8.91 (s, 1H),8.11 (s, 1H), 7.87 (dd, J=8, 1 Hz, 1H), 7.84 (d, J=1 Hz, 1H), 7.40 (m,6H), 7.08 (m, 2H), 6.80 (d, J=8 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 6.62 (s,1H), 6.43 (d, J=8 Hz, 1H), 5.16 (s, 2H), 4.21 (t, J=6 Hz, 4H), 3.83 (s,3H), 2.68 (m, 4H), 2.32 (quintet, J=6 Hz, 2H), 1.56 (hextet, J=8 Hz,2H), 1.21 (t, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H); TOF MS ES⁺ exact masscalculated for C₃₈I₄₀NO₆S (p+1): m/z=638.2576. Found: 638.2579. IR(CHCl₃, cm⁻¹) 2964, 1719, 1563, 1461.

[0209] B. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0210] A solution of2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-4-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester (243 mg, 0.366 mmol) in ethanethiol (7 mL) was treatedwith boron trifluoride etherate at room temperature for 4 h. The mixturewas diluted with diethyl ether, washed once with water, once withsaturated sodium bicarbonate solution, dried (sodium sulfate), filtered,and concentrated in vacuo. Chromatography (silica gel, 15% ethylacetate/85% hexane) of the residue provided 131 mg (65%) of the titlecompound as a colorless oil. ¹H NMR (CDCl₃) δ 8.88 (d, J=1 Hz, 1H), 7.88(dd, J=8, 1 Hz, 1H), 7.44 (d, J=1 Hz, 1H), 7.38 (m, 2H), 7.08 (m, 2H),6.81 (d, J=8 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J=8Hz, 1H), 4.21 (t, J=6 Hz, 4H), 3.83 (s, 3H)! 2.63 (m, 4H), 2.33(quintet, J=6 Hz, 2H), 1.56 (hextet, J=8 Hz, 2H), 1.19 (t, J=8 Hz, 3H),0.91 (t, J=7 Hz, 3H); TOF MS ES⁺ exact mass calculated for C₃₁H₃₄NO₆S(p+1): m/z 548.2107. Found: 548.2085.

[0211] C. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid.

[0212] A solution of2-{3-[3-(2-ethyl-5-hydroxy-4-thiazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (130 mg, 0.236 mmol) in methanol (4 mL) was treatedwith 1 M lithium hydroxide solution at 60° C. for 3 h. The mixture wascooled to room temperature, concentrated in vacuo, and diluted withwater. The solution was adjusted to pH ˜4 and extracted three times withmethylene chloride. The combined organic layers were dried (sodiumsulfate), filtered, and concentrated in vacuo. The residue was dissolvedin a minimum of methylene chloride and hexane was added until thesolution became cloudy. The mixture was concentrated slowly in vacuo togive 96 mg (76%) of the title compound. ¹H NMR (CDCl₃) δ 8.90 (s, 1H),8.23 (dd, J=8, 1 Hz, 1H), 7.41 (m, 2H), 7.38 (s, 1H), 7.29 (m, 2H), 6.82(d, J=8 Hz, 1H), 6.71 (d, J=8 Hz, 1H), 6.62 (d, J=8 Hz, 1H), 6.54 (s,1H), 4.25 (t, J=6 Hz, 2H), 4.22 (t, J=6 Hz, 2H), 2.59 (m, 4H), 2.35(quintet, J=6 Hz, 2H), 1.50 (hextet, J=8 Hz, 2H), 1.19 (t, J=7 Hz, 3H),0.88 (t, J=8 Hz, 3H); TOF MS ES⁺ exact mass calculated for C₃₀H₃₂NO₆S(p+1): m/z=534.1950. Found: 534.1957. IR (CHCl₃, cm⁻¹) 2965, 1738, 1454.

[0213] Anal. Calcd for C₃₀H₃₁NO₆S: C, 67.52; H, 5.86; N, 2.62. Found: C,67.19; H, 5.72; N, 2.53.

Example 4 Preparation of2-(3-{3-[2-Ethyl-5-hydroxy-4-(2H-pyrazol-3-yl)phenoxy]propoxy}-2-propyl-phenoxy)benzoicacid

[0214]

[0215] A. Preparation of2-(3-{3-[5-benzyloxy-4-(3-dimethylaminoacryloyl)-2-ethyl-phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0216] A mixture of2-(3-{3-[4-acetyl-5-benzyloxy-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (3.07 g, 5.04 mmol) and dimethylformamidedimethylacetal (0.9 mL, 7 mmol) in N,N-dimethylformamide (3 mL) washeated at 110-120° C. for 35 h. The mixture was cooled to roomtemperature and diluted with a mixture of ethyl acetate and 1 Nhydrochloric acid. The organic layer was separated, washed twice withwater, once with saturated sodium chloride solution, dried (sodiumsulfate), filtered, and concentrated in vacuo. Chromatography (silicagel, 30% ethyl acetate/70% hexane to ethyl acetate) of the residueprovided 2.1 g (63%) of the title compound as a yellow oil. TOF MS ES⁺exact mass calculated for C₄₀H₄₆NO₇ (p+1): m/z=652.3274. Found:652.3270. IR (CHCl₃, cm⁻¹) 2965, 1720, 1605.

[0217] Anal. Calcd for C₄₀H₄₅NO₇: C, 73.71; H, 6.96; N, 2.15. Found: C,73.72; H, 6.95; N, 2.18.

[0218] B. Preparation of2-(3-{3-[5-benzyloxy-2-ethyl-4-(2H-pyrazol-3-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid.

[0219] A solution of2-(3-{3-[5-benzyloxy-4-(3-dimethylaminoacryloyl)-2-ethyl-phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (550 mg, 0.843 mmol in methanol (30 mL) was treatedwith 1 M lithium hydroxide solution at 60° C. for 3 h. The mixture wascooled to room temperature and diluted with ethyl acetate and 0.5 Mhydrochloric acid. The organic layer was separated, washed withsaturated sodium chloride solution, dried (sodium sulfate), filtered,and concentrated in vacuo. The residue was dissolved in methanol (15 mL)and treated with water (4 mL) and hydrazine monohydrate (0.50 mL, 7.7mmol) at reflux for 3 h. The mixture was diluted with ethyl acetate and1 N hydrochloric acid. The organic layer was separated, washed withsaturated sodium chloride solution, dried (sodium sulfate), filtered andconcentrated in vacuo. Chromatography (30% ethyl acetate/69% hexane/1%acetic acid) of the residue provided 350 mg (65%) of the title compoundas the acetate salt. A portion of this material was free-based withsodium bicarbonate to provide an analytical sample. ¹H NMR (CDCl₃) δ8.20 (dd, J=8, 2 Hz, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 7.38 (m, 5H), 7.15(m, 2H), 6.78 (d, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 6.61 (d, J=8 Hz,1H), 6.58 (s, 1H), 6.55 (bs, 1H), 5.18 (s, 2H), 4.22 (t, J=6 Hz, 2H),4.17 (t, J=6 Hz, 2H), 2.58 (m, 4H), 2.30 (quintet, J=6 Hz, 2H), 1.47(hextet, J=8 Hz, 2H), 1.18 (t, J=7 Hz, 3H), 0.88 (t, J=8 Hz, 3H); TOF MSES⁺ exact mass calculated for C₃₇H₃₉N₂O₆ (p+1): m/z=607.2808. Found:607.2831. IR (CHCl₃, cm⁻¹) 2965, 1739, 1604, 1454.

[0220] Anal. Calcd for C₃₇H₃₈N₂O₆: C, 73.25; H, 6.31; N, 4.62. Found: C,73.31; H, 6.30; N, 4.62.

[0221] C. Preparation of2-(3-{3-[2-ethyl-5-hydroxy-4-(2H-pyrazol-3-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid.

[0222] A solution of2-(3-{3-[5-benzyloxy-2-ethyl-4-(2H-pyrazol-3-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid (300 mg, 0.490 mmol) in ethanethiol (2.5 mL) was treated with borontrifluoride etherate (2 mL) at room temperature for 3 h, at which timean additional portion of boron trifluoride etherate (1 mL) was added andstirring resumed for an additional 1 h. The mixture was diluted withdiethyl ether and water. The organic layer was separated, washed withwater, dried (sodium sulfate), filtered, and concentrated in vacuo.Chromatography (silica gel, 15% ethyl acetate/85% hexane to 60% ethylacetate/40% hexane) of the residue provided 60 mg (24%) of the titlecompound as a white solid.

[0223]¹H NMR (CDCl₃) δ 8.23 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.42 (t, J=7Hz, 1H), 7.30 (s, 1H), 7.19 (d, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 6.81(d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 6.61 (s, 1H), 6.60 (d, J=8 Hz,1H), 6.54 (s, 1H), 4.20 (m, 4H), 2.58 (m, 4H), 2.33 (quintet, J=6 Hz,2H), 1.48 (hextet, J=8 Hz, 2H), 1.17 (t, J=8 Hz, 3H), 0.86 (t, J=7 Hz,3H); TOF MS ES⁺ exact mass calculated for C₃₀H₃₃N₂O₆ (p+1):m/z=517.2339. Found: 517.2334.

[0224] IR (CHCl₃, cm⁻¹) 2965, 1738, 1454.

[0225] Anal. Calcd for C₃₀H₃₂N₂O₆: C, 69.75; H, 6.24; N, 5.42. Found: C.69.73; H, 6.33; N, 5.25.

Example 5 Preparation of2-{3-[3-(2-Ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid

[0226]

[0227] A. Preparation of2-{3-[3-(5-benzyloxy-2-ethyl-4-isoxazol-5-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0228] A mixture of2-(3-{3-[5-benzyloxy-4-(3-dimethylaminoacryloyl)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (280 mg, 0.43 mmol), hydroxylamine hydrochloride (75mg, 1.1 mmol), and water (1 mL) in methanol (4 mL) was heated at refluxfor 2 h. The mixture was cooled to room temperature and diluted withdiethyl ether and water. The organic layer was separated, washed withsaturated sodium chloride solution, dried (sodium sulfate), filtered,and concentrated in vacuo. Chromatography (silica gel, 10% ethylacetate/90% hexane) of the residue provided 202 mg (76%) of the titlecompound as a white solid. ¹H NMR (CDCl₃) δ 8.20 (d, J=2 Hz, 1H), 7.88(dd, J=9, 2 Hz, 1H), 7.79 (s, 1H), 7.40 (m, 7H), 7.08 (m, 2H), 6.68 (d,J=8 Hz, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 6.43 (d, J=8 Hz, 1H), 5.15 (s,2H), 4.21 (t, J=6 Hz, 4H), 3.82 (s, 3H), 2.65 (m, 4H), 2.33 (quintet,J=6 Hz, 2H), 1.56 (hextet, J=8 Hz, 2H), 1.20 (t, J=7 Hz, 3H), 0.90 (t,J=7 Hz, 3.H); TOF MS ES⁺ exact mass calculated for C₃₈H₄₀NO₇ (p+1):m/z=622.2805. Found: 622.2817. IR (CHCl₃, cm⁻¹) 2964, 1720, 1461.

[0229] Anal. Calcd for C₃₈H₃₉NO₇: C, 73.41; H, 6.32; N, 2.25. Found: C,73.20; H. 6.34; N, 2.27.

[0230] B. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0231] A solution of2-{3-[3-(5-benzyloxy-2-ethyl-4-isoxazol-5-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (180 mg, 0.289 mmol) in ethanethiol (5 mL) was treatedwith boron trifluoride etherate (1.5 mL) at room temperature for 2 h, atwhich time an additional portion of boron trifluoride etherate (0.5 mL)was added and stirring resumed for an additional 1 h. The mixture wasdiluted with diethyl ether and water. The organic layer was separated,washed once with saturated sodium bicarbonate solution, once withsaturated sodium chloride solution, dried (sodium sulfate), filtered,and concentrated in vacuo. Chromatography (silica gel, 15% ethylacetate/85% hexane) of the residue provided 94 mg (61%) of the titlecompound as a colorless oil. ¹H NMR (CDCl₃) δ 8.28 (d, J=1 Hz, 1H), 7.88(dd, J.=8, 2 Hz, 1H), 7.38 (t, J=8 Hz, 1H), 7.36 (s, 1H), 7.08 (t, J=8Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 6.67 (d, J=8 Hz,1H), 6.50 (s, 1H), 6.45 (s, 1H), 6.43 (d, J=8 Hz, 1H), 4.20 (m, 4H),3.83 (s, 3H), 2.62 (m, 4H), 2.34 (quintet, J=6 Hz, 2H), 1.54 (hextet,J=8 Hz, 2H), 1.18 (t, J=8 Hz, 3H), 0.90 (t, J=7 Hz, 3H); TOF MS ES⁺exact mass calculated for C₃₁H₃₄NO₇ (p+1): m/z=532.2335. Found:532.2335. IR (CHCl₃, cm⁻¹) 2964, 1715, 1601, 1461.

[0232] Anal. Calcd for C₃₁H₃₃NO₇: C, 70.04; H, 6.26; N, 2.63. Found: C,70.13; H, 6.35; N, 2.63.

[0233] C. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid.

[0234] To a solution of2-{3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (94 mg, 0.18 mmol) in methanol (3 mL) was added 1 Mlithium hydroxide solution (1 mL) and the resulting mixture warmed at60° C. for 3 h. The mixture was cooled to room temperature andconcentrated in vacuo. The aqueous residue was diluted with water andthe pH adjusted to ˜4. The mixture was extracted three times withmethylene chloride. The combined organic extracts were dried (sodiumsulfate), filtered, and concentrated in vacuo to provide 12 mg (13%) ofthe title compound as an off-white amorphous solid. ¹H NMR (CDCl₃) δ8.26 (s, 1H), 8.20 (dd, J=8, 1 Hz, 1H), 7.49 (t, J=6 Hz, 1H), 7.36 (s,1H), 7.18 (d, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 7.02 (bs, 1H), 6.80 (d,J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 6.60 (d, J=8.Hz, 1H), 6.50 (s, 1H),6.46 (s, 1H), 4.22 (t, J=6 Hz, 2H), 4.19 (t, J=6 Hz, 2H); 2.57 (m, 4H),2.34 (quintet, J=6 Hz, 2H), 1.47 (hextet, J=8 Hz, 2H), 1.16 (t, J=8 Hz,3H), 0.85 (t, J=7 Hz, 3H); TOS MS ES⁺ exact mass calculated forC₃₀H₃₂NO₇ (p+1): m/z=518.2179. Found: 518.2175.

[0235] Anal. Calcd for C₃₀H₃₁NO₇: C, 69.62; H, 6.04; N, 2.71. Found: C,69.57; H, 6.15; N, 2.74.

Example 6 Preparation of2-(3-{3-[2-Ethyl-5-hydroxy-4-(3H-[1,2,3]triazol-4-yl)phenoxy]propoxy)-2-propyl-phenoxy}benzoicacid

[0236]

[0237] A. Preparation of2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy]-2-propylphenoxy}-benzoicacid methyl ester.

[0238] A mixture of5-benzyloxy-4-bromo-1-(3-chloropropoxy)-2-ethylbenzene (1.19 g, 3.11mmol), 2-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester (0.89 g,3.1 mmol), potassium carbonate (1.29 g, 9.34 mmol), potassium iodide(0.52 g, 3.1 mmol), and methyl sulfoxide (2 mL) in 2-butanone (20 mL)was heated at reflux for 48 h. The mixture was cooled to roomtemperature, diluted with diethyl ether, and washed once with water. Theorganic layer was dried (sodium sulfate), filtered, and concentrated invacuo. Chromatography (silica gel, 6% ethyl acetate/94% hexane) of theresidue provided 1.34 g (68%) of the title compound as a colorless oil.¹H NMR (CDCl₃) δ 7.91 (dd, J=8, 2 Hz, 1H), 7.50 (d, J=7 Hz, 2H), 7.38(m, 5H), 7.15 (d, J=8 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 6.83 (d, J=8 Hz,1H), 6.71 (d, J=8 Hz, 1H), 6.55 (s, 1H), 6.48 (, J=8 Hz, 1H), 5.16 (s,2H), 4.21 (t, J=6 Hz, 2H), 4.15 (t, J=6 Hz, 2H), 3.83 (s, 3H), 2.68 (t,J=8 Hz, 2H), 2.58 (q, J=7 Hz, 2H), 2.31 (quintet, J=6 Hz, 2H), 1.58(hextet, J=6 Hz, 2H), 1.17 (t, J=7 Hz, 3H), 0.93 (t, J=7 Hz, 3H).

[0239] B. Preparation of2-{3-[3-(5-benzyloxy-2-ethyl-4-ethynylphenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester.

[0240] A mixture of2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy]-2-propylphenoxy}-benzoicacid methyl ester (1.50 g, 2.37 mmol), tri-n-butylethynyltin (0.82 mL,2.8 mmol), and tetrakis(triphenylphosphine)palladium (0) (1.0 g, 0.95mmol) in N,N-dimethylformamide (25 mL) was purged with argon and heatedin a sealed tube at 120° C. for 24 h. The mixture was cooled to roomtemperature and filtered. The filtrate was diluted with ethyl acetate,washed four times with water, once with saturated sodium chloridesolution, dried (sodium sulfate), filtered, and concentrated in vacuo.Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residueprovided 532 mg (39%) of the title compound as a brown oil. ¹H NMR(CDCl₃) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.79 (s, 1H), 7.20-7.50 (m, 6H),7.10 (d, J=8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.66(d, J=8 Hz, 1H), 6.43 (m, 2H), 5.16 (s, 2H), 4.17 (t, J=6 Hz, 2H), 4.11(t, J=6 Hz, 2H), 3.83 (s, 3H), 3.23 (s, 1H), 2.64 (t, J=8 Hz, 2H), 2.53(q, J=7 Hz, 2H), 2.27 (quintet, J=6 Hz, 2H), 1.53 (m, 2H), 1.13 (t, J=7Hz, 3H), 0.89 (t, J=7 Hz, 3H); TOF MS ES⁺ exact mass calculated forC₃₇H₃₉O₆ (p+1): m/z=579.2747. Found: 579.2739.

[0241] C. Preparation of2-(3-{3-[5-benzyloxy-2-ethyl-4-(3H-[1,2,3]triazol-4-yl)phenoxy]-propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0242] A mixture of2-{3-[3-(5-benzyloxy-2-ethyl-4-ethynylphenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester (517 mg, 0.893 mmol) and trimethylsilyl azide (3.0 mL,18 mmol) was heated in toluene (20 mL) in a sealed tube at 130° C. for120 h. The mixture was cooled to room temperature and concentrated invacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane to 50%ethyl acetate/50% hexane) of the residue provided 347 mg (88% based uponrecovered starting material) of the title compound as a brown solid. ¹HNMR (CDCl₃) δ 8.10 (bs, 1H), 7.89 (dd, J=8, 2 Hz, 1H), 7.76 (s, 1H),7.40 (m, 7H), 7.10 (d, J=8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.79 (d, J=8Hz, 1H), 6.67 (d, J=8 Hz, 1H), 6.62 (s, 1H), 6.43 (d, J=8 Hz, 1H), 5.18(s, 2H), 4.21 (m, 4H), 3.82 (s, 3H), 2.65 (m, 4H), 2.32 (quintet, J=6Hz, 2H), 1.56 (hextet, J=8 Hz, 2H), 1.21 (t, J=8 Hz, 3H), 0.90 (t, J=7Hz, 3H); TOF MS ES⁺ exact mass calculated for C₃₇H₄₀N₃O₆ (p+1):m/z=622.2917. Found: 622.2946. IR (CHCl₃, cm⁻¹) 3400, 1721, 1602, 1453.

[0243] Anal. Calcd for C₃₇H₃₉N₃O₆: C, 71.48; H, 6.32; N, 6.76. Found: C,70.28; H, 6.07; N, 6.54.

[0244] D. Preparation of2-(3-{3-[2-ethyl-5-hydroxy-4-(3H-[1,2,3]triazol-4-yl)phenoxy]-propoxy)-2-propyl-phenoxy}benzoicacid methyl ester.

[0245] A solution of2-(3-[3-[5-benzyloxy-2-ethyl-4-(3H-[1,2,3]triazol-4-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (330 mg, 0.531 mmol) in ethanethiol (9 mL) was treatedwith boron trifluoride etherate (2.0 mL, 16 mmol) for 1 h at roomtemperature and then with an additional portion of boron trifluorideetherate (1.0 mL) for 1 h. The mixture was diluted with diethyl etherand water. The organic layer was washed once with saturated sodiumbicarbonate solution, once with saturated sodium chloride solution,dried (sodium sulfate), filtered, and concentrated in vacuo.Chromatography (silica gel, 30% ethyl acetate/70% hexane to 50% ethylacetate/50% hexane) of the residue provided 180 mg (63%) of the titlecompound as a brown solid. ¹H NMR (CDCl₃) δ 7.97 (s, 1H), 7.88 (dd, J=8,2 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J=8 Hz, 1H),7.05 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 6.67 (d, J=8 Hz, 1H), 6.59(s, 1H), 6.43 (d, J=8 Hz, 1H), 4.20 (m, 4H), 3.83.(s, 3H), 2.63 (m, 4H),2.34 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=8 Hz, 2H), 1.19 (t, J=8 Hz,3H), 0.90 (t, J=7 Hz, 3H); TOF MS ES⁺ exact mass calculated forC₃₀H₃₄N₃O₆ (p+1): m/z=532.2447. Found: 532.2466. IR (CHCl₃, cm⁻¹) 2964,1718, 1453.

[0246] Anal. Calcd for C₃₀H₃₃N₃O₆: C, 67.78; H, 6.26; N, 7.90. Found: C,66.80; H, 6.02; N, 7.53.

[0247] E. Preparation of2-(3-{3-[2-ethyl-5-hydroxy-4-(3H-[1,2,3]triazol-4-yl)phenoxy]-propoxy}-2-propylphenoxy)benzoicacid.

[0248] A solution of2-(3-{3-[2-ethyl-5-hydroxy-4-(3H-[1,2,3]triazol-4-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (160 mg, 0.30 mmol) in methanol (5 mL) was treated 1 Nlithium hydroxide solution (1.5 mL) at 60° C. for 3.5 h. The mixture wascooled to room temperature, diluted with water, and adjusted to ˜pH 4.The resulting mixture was extracted three times with methylene chloride.The combined organic extracts were dried (sodium sulfate), filtered, andconcentrated in vacuo to provide 134 mg (86%) of the title compound as atan solid. ¹H NMR (DMSO-d) δ 14.98 (bs, 1H), 12.80 (bs, 1H), 10.02 (bs,1H), 8.17 (bs, 1H), 7.77 (dd, J=7, 2 Hz, 1H), 7.60 (bs, 1H), 7.47 (t,J=8 Hz, 1H), 7.18 (t, J=8 Hz, 1H), 7.14 (t, J=8 Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.68 (d, J=8 Hz, 1H), 6.57 (s, 1H), 6.35 (d, J=8 Hz, 1H), 4.22(t, J=6 Hz, 2H), 4.15 (t, J=6 Hz, 2H), 2.54 (m, 4H), 2.25 (quintet, J=6Hz, 2H), 1.45 (hextet, J=8 Hz, 2H), 1.11 (t, J=7 Hz, 3H), 0.81 (t, J=7Hz, 3H); TOF MS ES⁺ exact mass calculated for C₂₉H₃₂N₃O₆ (p+1):m/z=518.2291. Found: 518.2302.

[0249] IR (CHCl₃, cm⁻¹) 2965, 1738, 1454.

[0250] Anal. Calcd for C₂₉H₃₁N₃O₆: C, 67.30; H, 6.04; N, 8.12. Found: C,67.15; H, 5.98; N, 7.93.

Example 7 Preparation of2-{3-[3-(2-Ethyl-5-hydroxy-4-pyrrol-1-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester

[0251]

[0252] A. Preparation of 5-benzyloxy-2-ethyl-4-pyrrol-1-yl-phenol.

[0253] To a mixture of potassium nitrosodisulfonate (40.0 g, 149 mmol)and potassium hydrogen phosphate (10 g) in water (1.2 L) at roomtemperature was added a solution of 4-ethylbenzene-1,3-diol (10.0 g,2.37 mmol) and potassium hydrogen phosphate (10.5 g) in water (150 mL).The mixture was stirred for 15 min and adjusted to pH ˜3. The solutionwas extracted three times with diethyl ether. The organic layer wasdried (sodium sulfate), filtered, and concentrated in vacuo. The residuewas dissolved in acetonitrile (70 mL) and treated at room temperaturewith 65% 3-pyrroline (12 mL). The resulting mixture was stirred for 1 hand concentrated in vacuo, dissolved in ethyl acetate and hexane, andfiltered down a short column of silica gel. The resulting solution wasconcentrated in vacuo. The residue was dissolved inN,N-dimethylformamide (10 mL) and treated with benzyl bromide (0.85 mL,7.1 mmol) and potassium carbonate (960 mg, 6.9 mmol) at room temperaturefor 15 h. The mixture was diluted with ethyl acetate, washed four timeswith water, once with saturated sodium chloride solution, dried (sodiumsulfate), filtered, and concentrated in vacuo. Chromatography (silicagel, ethyl acetate/hexane gradient) of the residue provided 316 mg (2%)of the title compound. TOF MS ES⁺ exact mass calculated for C₁₉H₂₀NO₂(p+1): m/z=294.1494. Found: 294.1471.

[0254] B. Preparation of1-[2-benzyloxy-4-(3-chloropropoxy)-5-ethylphenyl]-1H-pyrrole.

[0255] A mixture of 5-benzyloxy-2-ethyl-4-pyrrol-1-yl-phenol (316 mg,1.08 mmol), potassium carbonate (223 mg, 1.62 mmol), and1-bromo-3-chloropropane (0.16 mL, 1.6 mmol) in N,N-dimethylformamide (5mL) was stirred at room temperature for 18 h. The mixture was dilutedwith ethyl acetate and water, washed four times with water, once withsaturated sodium chloride solution, dried (sodium sulfate), filtered,and concentrated in vacuo. Chromatography (silica gel, 5% ethylacetate/95% hexane) of the residue provided 314 mg (79%) of the titlecompound as a colorless oil. TOF MS ES⁺ exact mass calculated forC₂₂H₂₅NClO₂ (p+1): m/z 370.1574. Found: 370.1548.

[0256] C. Preparation of2-{3-[3-(5-benzyloxy-2-ethyl-4-pyrrol-1-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0257] A mixture of1-[2-benzyloxy-4-(3-chloropropoxy)-5-ethylphenyl]-1H-pyrrole (310 mg,0.85 mmol) and sodium iodide (140 mg, 0.94 mol) in 2-butanone (5 mL) washeated at reflux for 6 h. The mixture was cooled to room temperature,filtered, and concentrated in vacuo. The residue was dissolved inN,N-dimethylformamide (7 mL) and treated with2-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester (242 mg, 0.85mmol) and potassium carbonate (129 g, 93 mmol) at room temperature for15 h. The mixture was diluted with ethyl acetate and water, washed fourtimes with water, once with saturated sodium chloride solution, dried(sodium sulfate), filtered, and concentrated in vacuo. Chromatography(silica gel, 5% ethyl acetate/95% hexane) of the residue provided 196 mg(37%) of the title compound as a colorless oil. ¹H NMR (CDCl₃) δ 7.86(dd, J=8, 2 Hz, 1H), 7.37 (dt, J=8, 2 Hz, 1H), 7.30 (m, 5H), 7.07 (m,3H), 6.84 (m, 2H), 6.79 (d, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 6.58 (s,1H), 6.42 (d, J=8 Hz, 1H), 6.29 (m, 2H), 4.92 (s, 2H), 4.17 (t, J=6 Hz,2H), 4.15 (t, J=6 Hz, 2H), 3.83 (s, 3H), 2.65 (t, J=8 Hz, 2H), 2.58 (q,J=7 Hz, 2H), 2.30 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=8 Hz, 2H), 1.16(t, J=7 Hz, 3H), 0.80 (t, J=7 Hz, 3H); TOF MS ES⁺ exact mass calculatedfor C₃₉H₄₂NO₆ (p+1): m/z=620.3012. Found: 620.3021.

[0258] D. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-pyrrol-1-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester.

[0259] A solution of2-{3-[3-(5-benzyloxy-2-ethyl-4-pyrrol-1-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (195 mg, 0.315 mmol) in ethanethiol (5 mL) was treatedwith boron trifluoride etherate (1.3 mL, 9.5 mmol) at room temperaturefor 2.5 h. The mixture was diluted with diethyl ether and water. Theorganic layer was washed with saturated sodium bicarbonate solution,dried (sodium sulfate), filtered, and concentrated in vacuo.Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residueprovided 39 mg (23%) of the title compound as a colorless oil. ¹H NMR(CDCl₃) δ 7.89 (d, J=8 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 7.07 (m, 2H), 6.98(s, 1H), 6.68 (m, 3H), 6.65 (d, J=8 Hz, 1H), 6.57 (s, 1H), 6.42 (d, J=8Hz, 1H), 6.35 (m, 2H), 5.04 (bs, 1H), 4.19 (m, 2H), 3.83 (s, 3H), 2.64(t, J=8 Hz, 2H), 2.58 (q, J=7 Hz, 2H), 2.32 (quintet, J=6 Hz, 2H), 1.55(m, 2H), 1.14 (t, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H); TOF MS ES⁺ exactmass calculated for C₃₂H₃₆NO₆ (p+1): m/z=530.2543. Found: 530.2516.

Example 8 Preparation of2-(3-{3-[4-(3-Bromo-[1,2,4]thiadiazol-5-yl)-2-ethyl-5-hydroxyphenoxy]-propoxy)-2-propylphenoxy}benzoicacid

[0260]

[0261] A. Preparation of2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0262] A mixture of2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy-]-2-propylphenoxy}-benzoicacid methyl ester (8.30 g, 13.1 mmol), triethylamine (5.2 mL, 39 mmol),and PdCl₂(dppf) (320 mg, 0.39 mmol) in de-oxygenated toluene (80 mL) wastreated with a 1 M solution of 4,4,5,5-tetramethyl-[1,3,2]dioxaborolanein tetrahydrofuran (20 mL, 20 mmol) and heated at reflux for 6 h. Themixture was filtered down a short column of silica gel and the filtrateconcentrated in vacuo. Chromatography (silica gel, 35% ethyl acetate/65%hexane) of the residue provided a dark oil that was subjected to furtherchromatography (silica gel, hexane to 30% ethyl acetate/70% hexane) togive 7.70 g (84%) of the title compound. ¹H NMR (CDCl₃) δ 7.86 (dd, J=8,2 Hz, 1H), 7.60 (d, J=8 Hz, 2H), 7.47 (s, 1H), 7.34 (m, 3H), 7.24 (t,J=8 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 6.79 (d, J=9Hz, 1H), 6.66 (d, J=9 Hz, 1H), 6.47 (s, 1H), 6.43 (d, J=8 Hz, 1H), 5.07(s, 2H), 4.18 (m, 4H), 3.81 (s, 3H), 2.64 (t, J=8 Hz, 2H), 2.56 (q, J=7Hz, 2H), 2.30 (quintet, J=6 Hz, 2H), 1.53 (hextet, J=8 Hz, 2H), 1.34 (s,12H), 1.14 (t, J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H); TOF MS ES⁺ exact masscalculated for C₄₁H₅₃NBO₈ (p+NH₄): m/z=698.3864. Found: 698.3889. IR(CHCl₃, cm⁻¹) 2964, 1720, 1604, 1453.

[0263] Anal. Calcd for C₄₁H₄₉BO₈: C, 72.35; H, 7.26. Found: C, 72.30; H,7.12.

[0264] B. Preparation of2-(3-{3-[5-benzyloxy-4-(3-bromo-[1,2,4]thiadiazol-5-yl)-2-ethyl-phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0265] A mixture of2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (310 mg, 0.46 mmol),3-bromo-5-chloro-1,2,4-thiadiazole (120 mg, 0.60 mmol), cesium carbonate(300 mg, 0.92 mmol), and PdCl₂(dppf) (20 mg, 0.024 mmol) inde-oxygenated toluene (10 mL) was heated at 100° C. for 15 h. Themixture was diluted with a solution of 35% ethyl acetate/65% hexane andfiltered down a short column of silica gel. The filtrate wasconcentrated in vacuo. Chromatography (silica gel, hexane to 30% ethylacetate/70% hexane) of the residue provided 232 mg (70%) of the titlecompound. ¹H NMR (CDCl₃) δ 8.13 (s, 1H), 7.87 (dd, J=8, 2 Hz, 1H), 7.44(m, 2H), 7.37 (m, 4H), 7.08 (t, J=8, 1 Hz, 1H), 7.04 (d, J=9 Hz, 1H),6.78 (d, J=9 Hz, 1H), 6.66 (d, J=9 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J=8Hz, 1H), 5.28 (s, 2H), 4.21 (t, J=6 Hz, 2H), 4.19 (t, J=6 Hz, 2H), 3.81(s, 3H), 2.62 (m, 4H), 2.34 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=8 Hz,2H), 1.17 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H); MS ES⁺ m/e 717, 719.

[0266] C. Preparation of2-(3-{3-[4-(3-bromo-[1,2,4]thiadiazol-5-yl)-2-ethyl-5-hydroxyphenoxy]propoxy}-2-propylphenoxy)benzoicacid.

[0267] A solution of2-(3-{3-[5-benzyloxy-4-(3-bromo-[1,2,4]thiadiazol-5-yl)-2-ethyl-phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (230 mg, 0.31 mmol) in ethanethiol (4 mL) was treatedwith boron trifluoride etherate (0.32 mL, 2.5 mmol) at room temperaturefor 6 h, at which time an additional portion of boron trifluorideetherate was added and stirring continued for 7 h. The reaction mixturewas diluted with water, concentrated in vacuo, and extracted withdiethyl ether. The residue was dissolved in methanol (5 mL) and treatedwith 1 N lithium hydroxide solution (2 mL) at 65° C. for 1 h. Themixture was concentrated in vacuo and the residue diluted with water andadjusted to ˜pH 3 with 1 N hydrochloric acid. The resulting precipitatewas collected via vacuum filtration and dissolved in dilute aqueousbase. Reverse phase chromatography (1:1 acetonitrile/water) provided 43mg (23%) of the title compound as a yellow solid. ¹H NMR (DMSO-d₆) δ7.85 (s, 1H), 7.80 (dd, J=8, 2 Hz, 1H), 7.45 (m, 2H), 7.15 (m, 3H), 6.83(d, J=9 Hz, 1H), 6.80 (d, J=9 Hz, 1H), 6.62 (s, 1H), 6.35 (d, J=9 Hz,1H), 4.20 (m, 4H), 2.55 (m, 4H), 2.27 (quintet, J=5 Hz, 2H), 1.44(hextet, J=8 Hz, 2H), 1.13 (t, J=7 Hz, 3H), 0.81 (t, J=7 Hz, 3H), MS ES⁺m/e 551 (p+NH₄ ⁺−Br); IR (KBr, cm⁻¹) 2900, 1696, 1603, 1461.

[0268] Anal. Calcd for C₂₉H₂₉BrN₂O₆S: C, 56.77; H, 4.76; N, 4.56. Found:C, 56.63; H, 4.72; N, 3.98.

Example 9 Preparation of2-{3-[3-(2-Ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoicacid sodium salt

[0269] A. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0270] A mixture of2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (300 mg, 0.44 mmol), 2-bromothiophene (110 mg, 0.66mmol), cesium carbonate (300 mg, 2.17 mmol), and PdCl₂(dppf) (20 mg,0.024 mmol) in de-oxygenated toluene (10 mL) was heated at 105° C. for66 h. The mixture was cooled to room temperature and concentrated invacuo. The residue was dissolved in methylene chloride and filtered downa short column of silica gel. The filtrate was concentrated in vacuo.Chromatography (silica gel, 30% ethyl acetate/70% hexane) of the residueprovided an oil that was dissolved in ethanethiol (4 mL) and treatedwith boron trifluoride etherate (0.44 mL, 3.4 mmol) at room temperaturefor 3 h. The mixture was diluted with water and extracted with diethylether. The organic layer was dried (sodium sulfate), filtered, andconcentrated in vacuo. Chromatography (silica gel, hexane to 30% ethylacetate/70% hexane) of the residue provided 120 mg (50%) of the titlecompound as a yellow film. ¹H NMR (CDCl₃) δ 7.85 (dd, J=8, 2 Hz, 1H),7.35 (t, J=8 Hz, 1H), 7.15 (d, J=7 Hz, 1H), 7.03-7.15 (m, 5H), 6.80 (d,J=9 Hz, 1H), 6.66 (d, J=9 Hz, 1H), 6.51 (s, 1H), 6.42 (d, J=8 Hz, 1H),5.44 (bs, 1H), 4.18 (m, 4H), 3.82 (s, 3H), 2.62 (t, J=8 Hz, 2H), 2.58(q, J=7 Hz, 2H), 2.54 (quintet, J=6 Hz, 2H), 1.52 (hextet, J=8 Hz, 2H),1.16 (t, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H); MS ES⁻ m/e 545 (p−1).

[0271] B. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid sodium salt.

[0272] A solution of2-{3-[3-(2-ethyl-5-hydroxy-4-thiophen-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (120 mg, 0.22 mmol) in methanol (3 mL) was treatedwith 1 N lithium hydroxide solution (0.5 mL) at room temperature for 1 hand then with an additional portion of 1 N lithium hydroxide solution(0.75 mL) for 18 h. The mixture was heated at 50° C. then concentratedin vacuo. The residue was acidified with dilute hydrochloric acid andextracted with diethyl ether. The organic layer was washed once withwater and concentrated in vacuo. The residue was diluted with 1 N sodiumhydroxide solution (0.22 mL), diethyl ether, and toluene. The mixturewas concentrated in vacuo, dissolved in methylene chloride, andconcentrated in vacuo to provide 120 mg (98%) of the title compound as agreen film. ¹H NMR (DMSO-d₆) δ 7.71 (d, J=8 Hz, 1H), 7.42 (m, 2H), 7.31(m, 2H), 7.10 (m, 2H), 6.99 (m, 1H), 6.76 (t, J=7 Hz, 2H), 6.52 (s, 1H),6.30 (d, J=8 Hz, 1H), 4.16 (t, J=7 Hz, 2H), 4.07 (t, J=7 Hz, 2H), 2.50(m, 4H), 2.20 (m, 2H), 1.40 (m, 2H), 1.06 (t, J=8 Hz, 3H), 0.77 (t, J=7Hz, 3H); MS ES⁺ m/e 533 (p+1−Na⁺). IR (CHCl₃, cm⁻¹) 2900, 1738, 1604,1454.

Example 10 Preparation of2-(3-{3-[2-Ethyl-5-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)-phenoxy]propoxy}-2-propylphenoxy)benzoicacid

[0273]

[0274] A. Preparation of 4-iodo-1-methylpyrazole (Known compound: RN39806-90-1).

[0275] To a solution of 4-iodopyrazole (1.3 g, 6.8 mmol) in dioxane (10mL) was added iodomethane (0.42 mL, 6.8 mmol) and the resulting mixturestirred at room temperature for 96 h. The mixture was concentrated invacuo and the residue mixed with methylene chloride and filtered. Thefiltrate was concentrated in vacuo to provide 1.35 g (95%) of the titlecompound as a colorless oil. ¹H NMR (CDCl₃) δ 7.47 (s, 1H), 7.38 (s,1H), 3.90 (s, 3H).

[0276] B. Preparation of2-(3-{3-[5-benzyloxy-2-ethyl-4-(1-methyl-1H-pyrazol-4-yl)phenoxy]-propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0277] A mixture of2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (1.00 g, 1.47 mmol), 4-iodo-1-methylpyrazole (450 mg,2.16 mmol), cesium carbonate (1.20.g, 3.62 mmol), and PdCl₂(dppf) (72mg, 0.088 mmol) in de-oxygenated toluene (35 mL) was heated at 100° C.for 24 h. Additional portions of 4-iodo-1-methylpyrazole (˜30 mg) andPdCl₂(dppf) (˜30 mg) were added and heating continued at 100° C. for 40h. The mixture was cooled to room temperature, concentrated in vacuo,diluted with methylene chloride, and filtered down a short plug ofsilica gel. The filtrate was concentrated in vacuo. Chromatography(silica gel, 35% ethyl acetate/65% hexane to 65% ethyl acetate/35%hexane) of the residue provided 710 mg (76%) of the title compound. ¹HNMR (CDCl₃) δ 7.86 (dd, J=8, 2 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.37(m, 6H), 7.28 (s, 1H), 7.09 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 6.78(d, J=9 Hz, 1H), 6.67 (d, J=9 Hz, 1H), 6.56 (s, 1H), 6.42 (d, J=8 Hz,1H), 5.08 (s, 2H), 4.18 (t, J=6 Hz, 2H), 4.15 (t, J=6 Hz, 2H), 3.85 (s,3H), 3.81 (s, 3H), 2.63 (t, J=8 Hz, 2H), 2.59 (q, J=7 Hz, 2H), 2.30(quintet, J=6 Hz, 2H), 1.55 (hextet, J=8 Hz, 2H), 1.23 (t, J=7 Hz, 3H),0.89 (t, J=7 Hz, 3H).

[0278] C. Preparation of2-(3-{3-[2-ethyl-5-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)-phenoxy]propoxy}-2-propylphenoxy)benzoicacid.

[0279] A solution of2-(3-{3-[5-benzyloxy-2-ethyl-4-(1-methyl-1H-pyrazol-4-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (710 mg, 1.12 mmol) in ethanethiol (5 mL) was treatedwith boron trifluoride etherate (1.42 mL, 11.2 mmol) at room temperaturefor 20 h. The reaction mixture was diluted with water, concentrated invacuo, and extracted with diethyl ether. The organic layer was dried(magnesium sulfate), filtered, and concentrated in vacuo. The residuewas triturated twice with hexane and the residue dissolved in methanol(5 mL). This solution was treated with 1 N lithium hydroxide solution (5mL) at ˜95° C. for 2 h. The mixture was concentrated in vacuo and theresidue diluted with water, washed twice with diethyl ether, and theaqueous layer acidified with 1 N hydrochloric acid. The resultingsolution was extracted with diethyl ether. The organic layer was dried(magnesium sulfate), filtered, and concentrated in vacuo. Chromatography(silica gel, 10% methanol/90% methylene chloride) provided 338 mg (57%)of the title compound as a tan foam. ¹H NMR (DMSO-d₆) δ 12.85 (bs, 1H),9.50 (bs, 1H), 7.98 (s, 1H), 7.78 (m, 2H), 7.48 (dt, J=8, 2 Hz, 1H),7.44 (s, 1H), 7.18 (t, J=8 Hz, 1H), 7.13 (t, J=9 Hz, 1H), 6.79 (d, J=9Hz, 1H), 6.77 (d, J=9 Hz, 1H), 6.53 (s, 1H), 6.35 (d, J=9 Hz, 1H), 4.20(t, J=6 Hz, 2H), 4.08 (t, J=6 Hz, 2H), 3.85 (s, 3H), 2.50 (m, 4H), 2.24(quintet, J=5 Hz, 2H), 1.45 (hextet, J=8 Hz, 2H), 1.09 (t, J=7 Hz, 3H),0.82 (t, J=7 Hz, 3H); MS ES⁺ m/e 531 (p+1); IR (KBr, cm⁻¹) 2961, 1697,1602, 1460, 1222.

[0280] Anal. Calcd for C₃₁H₃₄N₂O₆: C, 70.17; H, 6.46; N, 5.28. Found: C,69.27; H, 6.08; N, 4.63.

Example 11 Preparation of2-{3-[3-(2-Ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoicacid

[0281]

[0282] A. Preparation of2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0283] A mixture of2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (960 mg, 1.41 mmol), 2-bromothiazole (0.25 mL, 2.8mmol), cesium carbonate (1.15 g, 3.52 mmol), and PdCl₂(dppf) (35 mg,0.040 mmol) in de-oxygenated toluene (35 mL) was heated at 60° C. for 16h then at 100° C. for 7 h. Additional portions of 2-bromothiazole (0.13mL) and PdCl₂(dppf) (˜30 mg) were added and heating continued at 100° C.for 72 h. The mixture was cooled to room temperature, concentrated invacuo, diluted with methylene chloride, and filtered down a short plugof silica gel. The filtrate was concentrated in vacuo. Chromatography(silica gel, hexane to 35% ethyl acetate/65% hexane) of the residueprovided 282 mg (31%) of the title compound. ¹H NMR (CDCl₃) δ 8.20 (s,1H), 7.86 (dd, J=8, 1 Hz, 1H), 7.82 (d, J=3 Hz, 1H), 7.49 (d, J=7 Hz,2H), 7.35 (m, 4H), 7.23 (d, J=3 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 7.04 (d,J=9 Hz, 1H), 6.78 (d, J=9. Hz, 1H), 6.65 (d, J=9 Hz, 1H), 6.57 (s, 1H),6.42 (d, J=8 Hz, 1H), 5.24 (s, 2H), 4.17 (m, 4H), 3.81 (s, 3H), 2.63 (m,4H), 2.33 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=.8 Hz, 2H), 1.19 (t,J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H).

[0284] B. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0285] A solution of2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (282 mg, 0.442 mmol) in ethanethiol (3 mL) was treatedwith boron trifluoride etherate (0.56 mL, 4.4 mmol) at room temperaturefor 3 h. The reaction mixture was diluted with water, concentrated invacuo, and extracted with diethyl ether. The organic layer was dried(magnesium sulfate), filtered, and concentrated in vacuo. Chromatography(silica gel, ethyl acetate/hexane) provided 107 mg (44%) of the titlecompound. ¹H NMR (CDCl₃) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.80 (d, J=4 Hz,1H), 7.35 (dt, J=8, 2 Hz, 1H), 7.28 (d, J=4 Hz, 1H), 7.24 (s, 1H), 7.09(dt, J=9, 2 Hz, 1H), 7.05 (t, J=9 Hz, 1H), 6.79 (d, J=9 Hz, 1H), 6.66(d, J=9 Hz, 1H), 6.61 (s, 1H), 6.42 (d, J=9 Hz, 1H), 4.24 (t, J=6 Hz,2H), 4.18 (t, J=6 Hz, 2H), 3.81 (s, 3H), 2.63 (t, J=7 Hz, 2H), 2.58 (q,J=7 Hz, 2H), 2.34 (quintet, J=6 Hz, 2H), 1.52 (hextet, J=8 Hz, 2H), 1.17(t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H); MS ES⁺ m/e 548 (p+1).

[0286] C. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid.

[0287]2-{3-[3-(2-Ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (107 mg, 0.196 mmol) was dissolved in a 1:1 solutionof methanol/dioxane (3 mL) and treated with 1 N lithium hydroxidesolution (1 mL) at 60° C. for 2 h. The mixture was concentrated in vacuoand the residue diluted with water, washed twice with diethyl ether, andthe aqueous layer acidified with 1 N hydrochloric acid. The resultingsolution was extracted twice with methylene chloride and the combinedorganic layers dried (magnesium sulfate), filtered, and concentrated invacuo. Trituration (hexane) of the residue provided 72 mg (69%) of thetitle compound as a tan powder. ¹H NMR (CDCl₃) δ 8.22 (dd, J=8, 2 Hz,1H), 7.70 (d, J=4 Hz, 1H), 7.41 (dt, J=8, 2 Hz, 1H), 7.35 (s, 1H), 7.18(m, 3H), 6.82 (d, J=9 Hz, 1H), 6.69 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz,1H), 6.55 (s, 1H), 4.22 (t, J=6 Hz, 2H), 4.21 (t, J=6 Hz, 2H), 2.57 (m,4H), 2.35 (quintet, J=6 Hz, 2H), 1.49 (hextet, J=8 Hz, 2H), 1.18 (t, J=7Hz, 3H), 0.86 (t, J=7 Hz, 3H); MS ES⁺ m/e 534 (p+1);. IR (KBr, cm⁻¹)2957, 1695, 1599, 1457.

[0288] Anal. Calcd for C₃₀H₃₁NO₆S: C, 67.52; H, 5.86; N, 2.62. Found: C,67.44; H, 5.95; N, 2.55.

Example 12 Preparation of2-(3-{3-[4-(3,5-Dimethylisoxazol-4-yl)-2-ethyl-5-hydroxyphenoxy]propoxy}-2-propylphenoxy)benzoicacid sodium salt

[0289]

[0290] A mixture of2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (305 mg, 0.448 mmol), 3,5-dimethyl-4-iodoisoxazole(110 mg, 0.493 mmol), cesium carbonate (293 mg, 0.899 mmol), andPdCl₂(dppf) (15 mg, 0.018 mmol) in de-oxygenated toluene (10 mL) washeated at 95° C. for 10 h. Additional portions of3,5-dimethyl-4-iodoisoxazole (110 mg), cesium carbonate (260 mg), andPdCl₂(dppf) (˜15 mg) were added and heating continued at 110° C. for 20h. The mixture was cooled to room temperature, concentrated in vacuo,diluted with methylene chloride, and filtered down a short plug ofsilica gel with 20% ethyl acetate/80% hexane. The filtrate wasconcentrated in vacuo. The resulting colorless oil was dissolved inmethylene chloride (4 mL), cooled to 0° C., and treated withiodotrimethylsilane (0.40 mL, 2.7 mmol). The resulting mixture wasallowed to warm to room temperature and stirred for 18 h. An additionalportion of iodotrimethylsilane (0.70 mL) was added and stirringcontinued for 72 h. The mixture was poured into dilute sodiumthiosulfate solution. The organic layer was separated, washed withwater, dried (sodium sulfate), filtered, and concentrated in vacuo. Theresulting foam was dissolved in a 1:1 mixture of tetrahydrofuran/1 Nhydrochloric acid (5 mL) and stirred at room temperature for 18 h. Themixture was concentrated in vacuo and treated with 1 equivalent 1 Nsodium hydroxide solution in ether. The resulting mixture wasconcentrated in vacuo to provide 59 mg (23%) of the title compound as anoff-white solid. ¹H NMR (DMSO-d₆) δ 7.40 (dd, J=9, 2 Hz, 1H), 7.13 (dt,J=8, 2 Hz, 1H), 6.97 (m, 2H), 6.79 (s, 1H), 6.68 (d, J=9 Hz, 1H), 6.65(d, J=9 Hz, 1H), 6.60 (s, 1H), 6.21 (d, J=8 Hz, 1H), 4.19 (t, J=6 Hz,2H), 4.01 (t, J=6 Hz, 2H), 2.66 (t, J=8 Hz, 2H), 2.48 (q, J=8 Hz, 2H),2.24 (s, 3H), 2.17 (quintet, J=6 Hz, 2H), 2.07 (s, 3 H), 1.49 (hextet,J=8 Hz, 2H), 1.07 (t, J=7 Hz, 3H), 0.85 (t, J=7 Hz, 3H); TOF MS ES⁺exact mass calculated for C₃₂H₃₆NO₇ (p+1): m/z=546.2492. Found:546.2514; IR (KBr, cm⁻¹) 3400, 1605, 1460.

Example 13 Preparation of2-{3-[3-(2-Ethyl-4-furan-2-yl-5-hydroxyphenoxy)propoxy]-2-propylphenoxy}-benzoicacid sodium salt

[0291]

[0292] A. Preparation of2-{3-[3-(4-bromo-2-ethyl-5-hydroxyphenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0293] A solution of2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy]-2-propylphenoxy}-benzoicacid methyl ester (2.50 g, 3.95 mmol) in methylene chloride (40 mL) wascooled to −70° C. and treated with boron tribromide (0.25 mL, 2.6 mmol).After 25 min the mixture was poured into cold water and the resultingmixture extracted, with methylene chloride. The combined organicextracts were washed once with water, once with saturated sodiumchloride solution, dried (sodium sulfate), filtered, and concentrated invacuo to provide 1.1 g (52%) of the title compound as a pale yellow oil.¹H NMR (CDCl₃) δ 7.89 (d, J=9 Hz, 1H), 7.38 (t, J=8 Hz, 1H), 7.18 (s1H), 7.12 (d, J=9 Hz, 1H), 7.08 (d, J=2 Hz, 1H), 6.81 (d, J=9 Hz, 1H),6.68 (d, J=9 Hz, 1H), 6.56 (s, 1H), 6.46 (d, J=9 Hz, 1H), 5.40 (s, 1H),4.18 (t, J=6 Hz, 2H), 4.11 (t, J=6 Hz, 2H), 3.84 (s, 3H), 2.65 (t, J.=8Hz, 2H), 2.54 (q, J=7 Hz, 2H), 2.32 (quintet, J=6 Hz, 2H), 1.54 (hextet,J=8 Hz, 2H), 1.13 (t, J=7 Hz, 3H), 0.89 (t, J=7 Hz, 3H); MS ES⁻ m/z=541(M−H), 543 (M−H +2).

[0294] B. Preparation of2-(3-{3-[4-bromo-5-(tert-butyldimethylsilanyloxy)-2-ethylphenoxy]-propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0295] A solution of2-{3-[3-(4-bromo-2-ethyl-5-hydroxyphenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (1.00 g, 1.84 mmol) in methylene chloride (20 mL) wastreated with imidazole (0.19 g, 2.8 mmol) and tert-butyldimethylsilylchloride (0.388 g, 2.57 mmol) at room temperature for 2 h. The mixturewas poured into water and the organic layer separated, washed once withwater, once with saturated sodium chloride solution, filtered through ashort pad of silica gel, and concentrated in vacuo to provide 1.1 g(91%) of the title compound as a colorless oil. ¹H NMR (CDCl₃) δ 7.88(d, J=9 Hz, 1H), 7.38 (t, J=8 Hz, 1H), 7.22 (s 1H), 7.12 (d, J=9 Hz,1H), 7.08 (d, J=2 Hz, 1H), 6.80 (d, J=9 Hz, 1H), 6.69 (d, J=9 Hz, 1H),6.45 (d, J=9 Hz, 1H), 6.40 (s, 1H), 4.20 (t, J=6 Hz, 2H), 4.11 (t, J=6Hz, 2H), 3.83 (s, 3H), 2.64 (t, J=8 Hz, 2H), 2.54 (q, J=7 Hz, 2H), 2.32(quintet, J=6 Hz, 2H), 1.54 (hextet, J=8 Hz, 2H), 1.13 (t, J=7 Hz, 3H),1.03 (s, 9H), 0.89 (t, J=7 Hz, 3H), 0.23 (s, 6H).

[0296] C. Preparation of2-{3-[3-(2-ethyl-4-furan-2-yl-5-hydroxyphenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester.

[0297] A mixture of2-(3-{3-[4-bromo-5-(tert-butyldimethylsilanyloxy)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (1.05 g, 1.60 mmol), furan-2-boronic acid (0.358 g,3.20 mmol), tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.160mmol), and 2 M aqueous sodium carbonate solution (8 mL) intetrahydrofuran (20 mL) was heated at reflux for 18 h. The mixture wascooled to room temperature, diluted with water, and extracted with ethylacetate. The organic layer was separated, washed once with water, oncewith saturated sodium chloride solution, dried (sodium sulfate),filtered, and concentrated in vacuo. Chromatography (silica gel, 10%ethyl acetate/90% hexane) of the residue provided 0.8 g (94%) of thetitle compound as a colorless oil. ¹H NMR (CDCl₃) δ 7.90 (d, J=9 Hz,1H), 7.48 (s, 1H), 7.38 (t, J=8 Hz, 1H), 7.21 (s 1H), 7.13 (s, 1H), 7.10(d, J=9 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 6.81 (d, J=9 Hz, 1H), 6.69 (d,J=9 Hz, 1H), 6.52 (m, 3H), 6.44 (d, J=9 Hz, 1H), 4.20 (m, 4H), 3.83 (s,3H), 2.67 (t, J=8 Hz, 2H), 2.59 (q, J=7 Hz, 2H), 2.32 (quintet, J=6 Hz,2H), 1.55 (hextet, J=8 Hz, 2H), 1.18 (t, J=7 Hz, 3H), 0.91 (t, J=7 Hz,3H); MS ES⁻ m/z=589 (p+AcO⁻).

[0298] Anal. Calcd for C₃₂H₃₄O₇: C, 72.43; H, 6.46. Found: C, 72.21; H,6.15.

[0299] D. Preparation of2-{3-[3-(2-ethyl-4-furan-2-yl-5-hydroxyphenoxy)propoxy]-2-propylphenoxy}benzoicacid sodium salt.

[0300]2-{3-[3-(2-Ethyl-4-furan-2-yl-5-hydroxyphenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (250 mg, 0.47 mmol) was dissolved in tetrahydrofuran(4 mL) and treated with 1 N lithium hydroxide solution (2 mL) at 50° C.for 16 h. The mixture was concentrated in vacuo and the residue dilutedwith water and extracted twice with ethyl acetate. The combined organicextracts were washed once with water, once with saturated sodiumchloride solution, dried (sodium sulfate), filtered, and concentrated invacuo. The residue was dissolved in ethyl acetate and shaken with 1 Nhydrochloric acid. The organic layer was dried (sodium sulfate),filtered, and concentrated in vacuo. The residue was dissolved indiethyl ether and treated with 1 N aqueous sodium hydroxide solution(0.32 mL). The mixture was concentrated in vacuo and azeotropedsuccessively with diethyl ether, chloroform, and diethyl ether and driedto provide 168 mg (66%) of the title product as a cream solid.

[0301]¹H NMR (DMSO-d₆) δ 7.56 (s, 1H), 7.44 (d, J=8 Hz, 1H), 7.35 (s,1H), 7.13 (m, 1H), 6.97 (m, 2H), 6.77 (d, J=2 Hz, 1H), 6.65 (m, 4H),6.48 (d, J=2 Hz, 1H), 6.24 (d, J=9 Hz, 1H), 4.15 (t, J=6 Hz, 2H), 3.96(t, J=6 Hz, 2H), 2.66 (t, J=8 Hz, 2H), 2.42 (q, J=7 Hz, 2H), 2.13(quintet, J=6 Hz, 2H), 1.48 (hextet, J=8 Hz, 2H), 1.09 (t, J=7 Hz, 3H),0.84 (t, J=7 Hz, 3H); TOF MS ES⁺ exact mass calculated for C₃₁H₃₃O₇(p+1): m/z=517.2226. Found: 517.2230. IR (KBr, cm⁻¹) 3400, 2961, 1599,1460.

Example 14 Preparation of2-(3-{3-[2-Ethyl-5-hydroxy-4-furan-3-yl]phenoxy]propoxy}-2-propylphenoxy)benzoicacid

[0302]

[0303] A. Preparation of2-{3-[3-(2-ethyl-4-furan-3-yl-5-hydroxyphenoxy)propoxy]-2-propyl-phenoxy}benzoicacid methyl ester.

[0304] A mixture of2-(3-{3-[4-bromo-5-(tert-butyldimethylsilanyloxy)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (2.10 g, 3.19 mmol), furan-3-boronic acid (0.722 g,6.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32mmol), and 2 M aqueous sodium carbonate solution (16 mL) intetrahydrofuran (30 mL) was heated at reflux for 48 h. The mixture wascooled to room temperature, diluted with water, and extracted with ethylacetate. The organic layer was separated, washed once with water, oncewith saturated sodium chloride solution, dried (sodium sulfate),filtered, and concentrated in vacuo. Chromatography (silica gel, 15%ethyl acetate/85% hexane) of the residue provided 0.29 g (17%) of thetitle compound as a yellow oil. TOF MS ES⁺ exact mass calculated forC₃₂H₃₅O₇ (p+1): m/z 531.2383. Found: 531.2396.

[0305] B. Preparation of2-{3-[3-(2-ethyl-4-furan-3-yl-5-hydroxyphenoxy)propoxy]-2-propylphenoxy}benzoicacid sodium salt.

[0306]2-{3-[3-(2-Ethyl-4-furan-3-yl-5-hydroxyphenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (170 mg, 0.32 mmol) was dissolved in tetrahydrofuran(4 mL) and methanol (1 mL) and treated with 1 N lithium hydroxidesolution (4 mL) at 50° C. for 2 h. The mixture was concentrated in vacuoand the residue acidified with hydrochloric acid and the resultingmixture extracted twice with ethyl acetate. The combined organicextracts were washed once with water, once with saturated sodiumchloride solution, dried (sodium sulfate), filtered, and concentrated invacuo. Chromatography (silica gel, 2% methanol/98% chloroform) of theresidue gave 45 mg of material that was again submitted tochromatography (silica gel, 1% methanol/99% chloroform) to provide 25 mg(15%) of the title compound as an oil.

[0307] TOF MS ES⁺ exact mass calculated for C₃₁H₃₃O₇ (p+1) m/z=517.226.Found: 517.2230.

Example 15 Preparation of2-(3-{3-[2-Ethyl-5-hydroxy-4-(tetrahydrofuran-3-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid sodium salt hemihydrate

[0308]

[0309] A. Preparation of2-{3-[3-(5-benzyloxy-2-ethyl-4-furan-3-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester.

[0310] A mixture of2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy]-2-propylphenoxy}-benzoicacid methyl ester (3.00 g, 4.73 mmol), furan-3-boronic acid (1.06 g,9.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.54 g, 0.47mmol), and 2 M aqueous sodium carbonate solution (20 mL) intetrahydrofuran (40 mL) was heated at 100° C. for 48 h. The mixture wascooled to room temperature, diluted with water, and extracted with ethylacetate. The organic layer was separated, washed once with water, oncewith saturated sodium chloride solution, dried (sodium sulfate),filtered, and concentrated in vacuo. Chromatography (silica gel, 10%ethyl acetate/90% hexane) of the residue provided 1.9 g (65%) of thetitle compound as a yellow oil. ¹H NMR (CDCl₃) δ 7.88 (dd, J=8, 2 Hz,1H), 7.87 (s, 1H), 7.40 (m, 7H), 7.26 (s 1H), 7.05 (m, 2H), 6.80 (d, J=9Hz, 1H), 6.76 (d, J=2 Hz, 1H), 6.67 (d, J=9 Hz, 1H), 6.60 (s, 1H), 6.43(d, J=9 Hz, 1H), 5.11 (s, 2H), 4.18 (m, 4H), 3.83 (s, 3H), 2.66 (t, J=8Hz, 2H), 2.62 (q, J=7 Hz, 2H), 2.30 (quintet, J=6 Hz, 2H), 1.57 (hextet,J=8 Hz, 2H), 1.20 (t, J=7 Hz, 3H), 0.92 (t, J=7 Hz, 3H); MS ES⁺ m/z=621(p+1); IR (CHCl₃, cm⁻¹) 3000, 1727, 1603, 1461.

[0311] B. Preparation of2-(3-{3-[2-ethyl-5-hydroxy-4-(tetrahydrofuran-3-yl)phenoxy]-propoxy}-2-propylphenoxy)benzoicacid methyl ester.

[0312] A solution of2-{3-[3-(5-benzyloxy-2-ethyl-4-furan-3-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid methyl ester (1.8 g, 2.9 mmol) in ethyl acetate (40 mL) was treatedwith 10% palladium-on-carbon (0.39 g) and hydrogenated at 48 psi and 45°C. for 72 h. The mixture was cooled to room temperature, filteredthrough Celite™, and the filtrate concentrated in vacuo to provide 1.2 g(77%) of the title compound as a colorless oil. ¹H NMR (CDCl₃) δ 7.88(dd, J=8, 2 Hz, 1H), 7.57 (dt, J=8, 2 Hz, 1H), 7.09 (d, J=9 Hz, 1H),7.04 (d, J=9 Hz, 1H), 6.81 (d, J=9 Hz, 1H), 6.80 (s, 1H), 6.67 (d, J=9Hz, 1H), 6.44 (d, J=9 Hz, 1H), 6.43 (s, 1H), 4.19 (m, 3H), 4.10 (m, 2H),4.02 (dd, J=12, 3 Hz, 1H), 3.88 (dd, J=12, 8 Hz, 1H), 3.84 (s, 3H), 3.73(q, J=9 Hz, 1H), 3.45 (m, 1H), 2.64 (t, J=8 Hz, 2H), 2.53 (q, J=7 Hz,2H), 2.38 (m, 1H), 2.28 (quintet, J=6 Hz, 2H), 1.99 (m, 1H), 1.55(hextet, J=8 Hz, 2H), 1.15 (t, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H); MS ES⁻m/z=593 (p+CH₃COO⁻); IR (CHCl₃, cm⁻¹) 2963, 1719, 1589, 1461.

[0313] Anal. Calcd for C₃₂H₃₈O₇: C, 71.89; H, 7.16. Found: C, 71.41; H,7.06.

[0314] C. Preparation of2-(3-{3-[2-ethyl-5-hydroxy-4-(tetrahydrofuran-3-yl)phenoxy]-propoxy}-2-propylphenoxy)benzoicacid sodium salt hemihydrate.

[0315] A solution of2-(3-{3-[2-ethyl-5-hydroxy-4-(tetrahydrofuran-3-yl)phenoxy]propoxy}-2-propylphenoxy)benzoicacid methyl ester (0.92 g, 1.7 mmol) in tetrahydrofuran (10 mL) andmethanol (5 mL) was treated with 1 M aqueous lithium hydroxide solution(10 mL) at 55° C. for 2 h. The mixture was allowed to cool to roomtemperature and stirred for an additional 18 h. The mixture wasconcentrated in vacuo and the remaining aqueous mixture was washed oncewith diethyl ether. The aqueous layer was acidified with concentratedhydrochloric acid and the resulting solution extracted with ethylacetate. The ethyl acetate layer was washed once with water, once withsaturated sodium chloride solution, dried (sodium sulfate), filtered,and concentrated in vacuo. The resulting colorless oil was dissolved indiethyl ether and treated with 1 N aqueous sodium hydroxide solution(1.72 mL). The resulting biphasic mixture was diluted with chloroformand concentrated in vacuo. Diethyl ether was added and the mixtureconcentrated in vacuo. The resulting white foam was dried in vacuo atroom temperature for 60 h to provide 0.78 g (84%) of the title compound:mp 67-71° C.

[0316]¹H NMR (DMSO-d₆) δ 7.62 (dd, J=8, 2 Hz, 1H), 7.30 (dt, J=8, 2 Hz,1H), 7.05 (m, 2H), 6.85 (s, 1H), 6.73 (d, J=9 Hz, 1H), 6.70 (d, J=9 Hz,1H), 6.53 (s, 1H), 6.34 (d, J=9 Hz, 1H), 4.15 (t, J=6 Hz, 2H), 4.04 (t,J=6 Hz, 2H), 3.95 (m, 1H), 3.88 (m, 1H), 3.75 (q, J=9 Hz, 1H), 3.49 (m2H), 2.60 (t, J=8 Hz, 2H), 2.45 (q, J=7 Hz, 2H), 2.15 (m, 3H), 1.90 (m,1H), 1.48 (hextet, J=8 Hz, 2H), 1.06 (t, J=7 Hz, 3H), 0.83 (t, J=7 Hz,3H); MS ES⁻ m/z=519 (p−Na⁺); IR (CHCl₃, cm⁻¹) 2964, 1783, 1604, 1461.

[0317] Anal. Calcd for C₃₁H₃₅NaO₇.0.5H₂O: C, 67.50; H, 6.58. Found: C,67.76; H, 6.68.

Example 16 Preparation of2-{3-[3-(2-Ethyl-5-hydroxy-4-pyrrolidin-2-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoicacid hydrochloride hydrate

[0318]

[0319] A. Preparation of2-(2-benzyloxy-5-ethyl-4-{3-[3-(2-methoxycarbonylphenoxy)-2-propylphenoxy]propoxy}phenyl)pyrrole-1-carboxylicacid tert-butyl ester.

[0320] A mixture of2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy]-2-propylphenoxy}-benzoicacid methyl ester (3.00 g, 4.73 mmol), N-boc pyrrole-2-boronic acid(1.99 g, 9.43 mmol), tetrakis(triphenylphosphine)palladium(0) (0.54 g,0.47 mmol), and 2 M aqueous sodium carbonate solution (25 mL) intetrahydrofuran (60 mL) was heated at reflux for 40 h. The mixture wascooled to room temperature, diluted with water, and extracted with ethylacetate. The organic layer was separated, washed once with water, oncewith saturated sodium chloride solution, dried (sodium sulfate),filtered, and concentrated in vacuo. Chromatography (silica gel, 10%ethyl acetate/90% hexane) of the residue provided 2.6 g (76%) of thetitle compound as a solid. ¹H NMR (CDCl₃) δ 7.88 (dd, J=8, 2 Hz, 1H),7.15-7.40 (m, 7H), 7.08 (m, 3H), 6.82 (d, J=9 Hz, 1H), 6.68 (d, J=9 Hz,1H), 6.52 (s, 1H), 6.44 (d, J=9 Hz, 1H), 6.23 (t, J=4 Hz, 1H), 6.12 (m,1H), 4.95 (s, 2H), 4.20 (t, J=6 Hz, 2H); 4.15 (t, J=6 Hz, 2H), 3.84 (s,3H), 2.66 (t, J=8 Hz, 2H), 2.60 (q, J=7 Hz, 2H), 2.30 (quintet, J=6 Hz,2H), 1.57 (hextet, J=8 Hz, 2H), 1.28 (s, 9H), 1.18 (t, J=7 Hz, 3H), 0.93(t, J=7 Hz, 3H); TOS MS ES⁺ exact mass calculated for C₄₄H₅₃N₂O₈ (p+NH₄⁺): m/z=737.3802. Found: 737.3804;

[0321] IR (CHCl₃, cm⁻¹) 2964, 1730, 1461.

[0322] Anal. Calcd for C₄₄H₄₉NO₈: C, 73.41; H. 6.86; N, 1.94. Found: C,73.76; H, 6.76; N, 2.04.

[0323] B. Preparation of2-(5-ethyl-2-hydroxy-4-{3-[3-(2-methoxycarbonylphenoxy)-2-propylphenoxy]propoxy}phenyl)-pyrrolidine-1-carboxylicacid tert-butyl ester.

[0324] A solution of2-(2-benzyloxy-5-ethyl-4-{3-[3-(2-methoxycarbonylphenoxy)-2-propylphenoxy]propoxy}phenyl)pyrrole-1-carboxylicacid tert-butyl ester (0.98 g, 1.4 mmol) in ethyl acetate (40 mL) wastreated with 10% palladium-on-carbon (0.98 g) and hydrogenated at 45 psiand 45° C. for 25 h, at room temperature for 20 h, then at 45° C. for 19h. The mixture was cooled to room temperature, filtered through Celite™,and the filtrate concentrated in vacuo to provide 0.76 g (88%) of thetitle compound as a colorless oil. ¹H NMR (CDCl₃) δ 7.87 (dd, J=8, 2 Hz,1H), 7.37 (dt, J=8, 2 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz,1H), 6.91 (s, 1H), 6.81 (d, J=9 Hz, 1H), 6.67 (d, J=9 Hz, 1H), 6.47 (s,1H), 6.44 (d, J=9 Hz, 1H), 5.09 (m, 1H), 4.18 (d, J=6 Hz, 2H), 4.14 (t,J=6 Hz, 2H), 3.84 (s, 3H), 3.45 (m, 2H), 2.64 (t, J=8 Hz, 2H), 2.54 (m,3H), 2.25 (m, 5H), 2.06 (m, 1H), 1.54 (hextet, J=8 Hz, 2H), 1.43 (s,9H), 1.15 (t, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H).

[0325] C. Preparation of2-(4-{3-[3-(2-carboxyphenoxy)-2-propylphenoxy]propoxy}-5-ethyl-2-hydroxyphenyl)pyrrolidine-1-carboxylicacid tert-butyl ester lithium salt hydrate.

[0326] A solution of2-(5-ethyl-2-hydroxy-4-{3-[3-(2-methoxycarbonylphenoxy)-2-propylphenoxy]propoxy}phenyl)pyrrolidine-1-carboxylicacid tert-butyl ester (0.114 g, 0.18 mmol) in a 1:1 mixture ofmethanol/tetrahydrofuran (4 mL) was treated with solution of 1 M lithiumhydroxide (4 mL) at room temperature for 18 h. The mixture wasconcentrated in vacuo and the residue dissolved in water. The resultingmixture was extracted with ethyl acetate. The organic extract was dried(sodium sulfate), filtered, and concentrated in vacuo. The residue wasdiluted with diethyl ether, concentrated in vacuo, and dried to provide90 mg (78%) of the title compound. MS ES⁺ m/z=620 (p+1−Li⁺); IR (KBr,cm⁻¹) 2964, 1672, 1603, 1416.

[0327] Anal. Calcd for C₃₆H₄₄NO₈Li.H₂O: C, 67.17; H, 7.20; N, 2.18.Found: C, 66.72; H, 6.99; N, 2.27.

[0328] D. Preparation of2-{3-[3-(2-ethyl-5-hydroxy-4-pyrrolidin-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoicacid hydrochloride hydrate.

[0329] Into a solution of2-(4-{3-[3-(2-carboxyphenoxy)-2-propylphenoxy]propoxy}-5-ethyl-2-hydroxyphenyl)pyrrolidine-1-carboxylicacid tert-butyl ester lithium salt hydrate (0.100 g, 0.16 mmol) inanhydrous diethyl ether (5 mL) was bubbled gaseous HCl. The resultingmixture was allowed to stir for 1 h. The mixture was concentrated invacuo. Chromatography (SCX cation exchange resin, 1:1tetrahydrofuran/methanol to dilute ammonia/methanol) of the residueprovided a tan solid. This material was dissolved in ether and treatedwith gaseous HCl. This mixture was concentrated in vacuo to provide 48mg (52%) of the title compound. ¹H NMR (DMSO-d₆) δ 12.80 (bs, 1H), 10.12(s, 1H), 9.34 (bs, 1H), 8.36 (bs, 1H), 7.79 (dd, J=9, 2 Hz, 1H), 7.47(dt, J=8, 2 Hz, 1H), 7.17 (t, J=8 Hz, 1H), 7.12 (d, J=9 Hz, 1H), 7.07(s, 1H), 6.80 (d, J=9 Hz, 1H), 6.78 (d, J=9 Hz, 1H), 6.58 (s, 1H), 6.35(d, J=9 Hz, 1H), 4.56 (m, 1H), 4.20 (t, J=6 Hz, 2H); 4.11 (t, J=6 Hz,2H), 3.25 (m, 2H), 2.50 (m, 5H), 1.90-2.60 (m, 5H), 1.44 (hextet, J=8Hz, 2H), 1.08 (t, J=7 Hz, 3H), 0.82 (t, J=7 Hz, 3H); TOS MS ES⁺ exactmass calculated for C₃₁H₃₈NO₆ (p+1): m/z=520.2699. Found: 520.2672.

Example 17 Preparation of2-{3-[3-(2-Ethyl-5-hydroxy-4-thiophen-3-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoicacid hydrate

[0330]

[0331] Known compound:

[0332] Sawyer et al., J. Med. Chem. 1995, 38, 4411.

[0333] A. Preparation of3-[2-benzyloxy-4-(3-chloropropoxy)-5-ethylphenyl]thiophene. A mixture of4-(benzyloxy)-5-bromo-2-(3-chloropropoxy)ethylbenzene (1.90 g, 5.30mmol), 3-thiopheneboronic acid (2.00 g, 15.9 mmol),tetrakis(triphenylphosphine)palladium(0) (312 mg, 0.270 mmol), 2 Maqueous sodium carbonate solution (4 mL), and n-propanol (4 mL) intoluene (16 mL) was refluxed for 4 h. The mixture was cooled to roomtemperature, diluted with diethyl ether, washed once with water and oncewith saturated sodium chloride solution. The organic layer was dried(magnesium sulfate), filtered, and concentrated in vacuo. Chromatography(silica gel, 5% ethyl acetate/95% hexane) of the residue provided 1.54 g(80%) of the title product as a white solid: mp 65-67° C. ¹H NMR (CDCl₃)δ 7.58 (d, J=2.8 Hz, 1H), 7.49 (d, J=5.2 Hz, 1H), 7.45-7.30 (m, 7H),6.62 (s, 1H), 5.13 (s, 2H), 4.14 (t, J=5.8 Hz, 2H), 3.81 (t, J=6.3 Hz,2H), 2.66 (q, J=7.5 Hz, 2H), 2.29 (quintet, J=6.0 Hz, 2H), 1.24 (t,J=7.5 Hz, 3H); MS FD m/e 386 (p); IR (CHCl₃, cm⁻¹) 2969, 1613, 1501,1138.

[0334] Anal. Calcd for C₂₂H₂₃O₂ClS: C, 68.29; H, 5.99. Found: C, 68.53;H, 6.00.

[0335] B. Preparation of2-[2-propyl-3-[3-[5-(benzyloxy)-2-ethyl-4-(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile.

[0336] A mixture of4-(benzyloxy)-2-(3-chloropropoxy)-5-(thiophen-3-yl)ethylbenzene (1.25 g,3.23 mmol), 3-(2-cyanophenoxy)-2-propylphenol (0.82 g, 3.2 mmol),potassium iodide (0.21 g, 1.3 mmol), potassium carbonate (1.12 g, 8.08mmol), and methyl sulfoxide (2 mL) in 2-butanone (10 mL.) was refluxedfor 60 h. The mixture was cooled to room temperature, diluted withether, and washed with water. The organic layer was dried (magnesiumsulfate), filtered, and concentrated in vacuo. Chromatography (silicagel, 5% ethyl acetate/95% hexane) of the residue provided 1.31 g (67%)of the title product as a colorless oil. ¹H NMR (CDCl₃) δ 7.66 (d, J=7.8Hz, 1H), 7.57 (d, J=2.9 Hz, 1H), 7.48 (d, J=5.2 Hz, 1H), 7.45-7.25 (m,8H), 7.20 (t, J=8.2 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 6.82 (d, J=8.3 Hz,1H), 6.77 (d, J=8.6 Hz, 1H), 6.64 (s, 1H), 6.63 (d, J=6.4 Hz, 1H), 5.11(s, 2H), 4.26 (t, J=6.0 Hz, 2H), 4.22 (t, J=6.0 Hz, 2H), 2.65 (m, 4H),2.36 (quintet, J=5.9 Hz, 2H), 1.58 (hextet, J=7.5 Hz, 2H), 1.24 (t,J=7.5 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS FD m/e 603 (p); IR (CHCl₃,cm⁻¹) 2967, 2250, 1613, 1501. Anal. Calcd for C₃₈H₃₇NO₄S: C, 75.59; H,6.18; N, 2.32. Found: C, 74.65; H, 6.21; N, 2.57.

[0337] C. Preparation of2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile.

[0338] To a solution of2-[2-propyl-3-[3-[5-(benzyloxy)-2-ethyl-4-(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile(900 mg, 1.49 mmol) in methylene chloride (25 mL) cooled to −78° C. wasadded 1 M boron tribromide solution in methylene chloride (2.99 mL, 2.99mmol) over 2 min. The resulting deep violet solution was stirred for 30min and allowed to warm to room temperature. The mixture was dilutedwith water and shaken. The organic layer was separated, dried (magnesiumsulfate), filtered, and concentrated in vacuo. Chromatography (silicagel, 25% ethyl acetate, 75% hexane) provided 400 mg (52%) of the titleproduct as a colorless oil. ¹H NMR (CDCl₃) δ 7.84 (d, J=4.8 Hz, 1H),7.71 (d, J=4.9 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.62 (s, 1H), 7.42 (t,J=7.1 Hz, 1H), 7.27 (t, J=6.6 Hz, 1H), 7.20 (s, 1H), 7.08 (t, J=6.9 Hz,1H), 6.85 (s, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 6.60(d, J=7.6 Hz, 1H), 4.71 (s, 1H, —OH), 4.26 (t, J=6.0 Hz, 4H), 2.72 (q,J=7.4 dHz, 2H), 2.59 (t, J=7.3 Hz, 2H), 2.39 (quintet, J=6.1 Hz, 2H),1.54 (hextet, J=7.7 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H), 0.91 (t, J=7.4 Hz,3H).

[0339] D. Preparation of2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzoicacid hydrate.

[0340] A solution of2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile(400 mg, 0.780 mmol) in 2:1 methanol/water (6 mL) was treated with 12.5M aqueous sodium hydroxide (4.0 mL) at reflux for 36 h. The mixture wascooled to room temperature, diluted with water, and extracted once withdiethyl ether. The aqueous layer was acidified with concentratedhydrochloric acid and extracted twice with methylene chloride. Thecombined methylene chloride layers were dried (magnesium sulfate),filtered, and concentrated in vacuo to provide a tan solid: mp 90-95° C.(dec). ¹H NMR (CDCl₃) δ 8.24 (d, J=7.8 Hz, 1H), 7.47 (d, J=5.0 Hz, 1H),7.44 (t, J=8.6 Hz, 1H), 7.36 (d, J=3 Hz, 1H), 7.24 (d, J=4.9 Hz, 1H),7.19 (m, 2H), 7.09 (s, 1H), 6.84 (d, J=8.0.Hz, 1H), 6.73 (d, J=8.3 Hz,1H), 6.64 (d, J=8.0 Hz, 1H), 6.55 (s, 1H), 5.38 (bs, 1H, —OH), 4.26 (t,J=6.2 Hz, 2H), 4.21 (t, J=7.1 Hz, 2H), 2.60 (m, 4H), 2.36 (quintet,J=5.8 Hz, 2H), 1.51 (hextet, J=7.1 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H), 0.90(t, J=7.4 Hz, 3H); MS FD m/e 532 (p); IR (KBr, cm⁻¹) 3200 (br), 2961,1697, 1457, 1110. Anal. Calcd for C₃₁H₃₂O₆S.H₂O: C, 67.62; H, 6.22.Found: C, 67.34; H, 5.87.

VI. Pharmaceutical Compositions of the Invention

[0341] Preferably compounds of the invention (per Formulae I or II) orpharmaceutical formulations containing these compounds are in unitdosage form for administration to a mammal. The unit dosage form can bea capsule, an IV bag, a tablet, or a vial. The quantity of ActiveIngredient in a unit dose of composition is a therapeutically effectiveamount and may be varied according to the particular treatment involved.It may be appreciated that it may be necessary to make routinevariations to the dosage depending on the age and condition of thepatient. The dosage will also depend on the route of administration.

[0342] The compound can be administered by a variety of routes includingoral, aerosol, rectal, transdermal, subcutaneous, intravenous,intramuscular, and intranasal.

[0343] Pharmaceutical formulations of the invention are prepared bycombining (e.g., mixing) a therapeutically effective amount of thecompounds of the invention (e.g., compounds of Formula I, II) togetherwith a pharmaceutically acceptable carrier or diluent therefor. Thepresent pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients.

[0344] In making the compositions of the present invention, the ActiveIngredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, lyophilzed solid or paste, semi-solid, orliquid material which acts as a vehicle, or can be in the form oftablets, pills, powders, lozenges, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium), orointment, containing, for example, up to 10% by weight of the activecompound. The compounds of the present invention are preferablyformulated prior to administration.

[0345] For the pharmaceutical formulations any suitable carrier known inthe art can be used. In such a formulation, the carrier may be a solid,liquid, or mixture of a solid and a liquid. For example, for intravenousinjection the compounds of the invention may be dissolved in at aconcentration of about 0.05 to about 5.0 mg/ml in a 4% dextrose/0.5% Nacitrate aqueous solution.

[0346] Solid form formulations include powders, tablets and capsules. Asolid carrier can be one or more substances which may also act asflavoring agents, lubricants, solubilisers, suspending agents, binders,tablet disintegrating agents and encapsulating material.

[0347] Tablets for oral administration may contain suitable excipientssuch as calcium carbonate, sodium carbonate, lactose, calcium phosphate,together with disintegrating agents, such as maize, starch, or alginicacid, and/or binding agents, for example, gelatin or acacia, andlubricating agents such as magnesium stearate, stearic acid, or talc.

[0348] In powders the carrier is a finely divided solid which is inadmixture with the finely divided Active Ingredient. In tablets theActive Ingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

[0349] Advantageously, compositions containing the compound of Formula(I) may be provided in dosage unit form, preferably each dosage unitcontaining from about 5 to about 500 mg (from about 5 to 50 mg in thecase of parenteral or inhalation administration, and from about 25 to500 mg in the case of oral or rectal administration. Dosages from about0.5 to about 300 mg/kg per day, preferably 0.5 to 20 mg/kg, of ActiveIngredient may be administered although it will, of course, readily beunderstood that the amount of the compound or compounds of Formula Iactually to be administered will be determined by a physician, in thelight of all the relevant circumstances.

[0350] Powders and tablets preferably contain from about 1 to about 99weight percent of the Active Ingredient which is the novel compound ofthis invention. Suitable solid carriers are magnesium carbonate,magnesium stearate, talc, sugar lactose, pectin, dextrin, starch,gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose,low melting waxes, and cocoa butter.

[0351] Sterile liquid form formulations include suspensions, emulsions,syrups and elixirs.

[0352] The Active Ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent or a mixture of both. By “pharmaceutically acceptable”it is meant the carrier, diluent or excipient must be compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

[0353] The Active Ingredient can also be dissolved in a suitable organicsolvent, for instance aqueous propylene glycol. Other compositions canbe made by dispersing the finely divided Active Ingredient in aqueousstarch or sodium carboxymethyl cellulose solution or in a suitable oil.

[0354] The following pharmaceutical formulations 1 to 8 are illustrativeonly and are not intended to limit the scope of the invention in anyway. “Active Ingredient”, refers to a compound according to Formula (I)or (II) or a pharmaceutically acceptable salt, solvate, or prodrugthereof.

Formulation 1

[0355] Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Active Ingredient 250 Starch, dried200 Magnesium stearate  10 Total 460 mg

Formulation 2

[0356] A tablet is prepared using the ingredients below: Quantity(mg/tablet) Active Ingredient 250 Cellulose, microcrystalline 400Silicon dioxide, fumed  10 Stearic acid  5 Total 665 mg

[0357] The components are blended and compressed to form tablets eachweighing 665 mg

Formulation 3

[0358] An aerosol solution is prepared containing the followingcomponents: Weight Active Ingredient 0.25 Ethanol 25.75 Propellant 22(Chlorodifluoromethane) 74.00 Total 100.00

[0359] The Active Ingredient is mixed with ethanol and the mixture addedto a portion of the propellant 22, cooled to −30° C. and transferred toa filling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

[0360] Formulation 4

[0361] Tablets, each containing 60 mg of Active Ingredient, are made asfollows: Active Ingredient   60 mg Starch   45 mg Microcrystallinecellulose   35 mg Polyvinylpyrrolidone (as 10% solution in water)   4 mgSodium carboxymethyl starch  4.5 mg Magnesium stearate  0.5 mg Talc   1mg Total  150 mg

[0362] The Active Ingredient, starch and cellulose are passed through aNo. 45 mesh U.S. sieve (355 μm) and mixed thoroughly. The aqueoussolution containing polyvinylpyrrolidone is mixed with the resultantpowder, and the mixture then is passed through a No. 14 mesh U.S. sieve(1.4 mm). The granules so produced are dried at 50° C. and passedthrough a No. 18 mesh U.S. sieve (1.00 mm). The sodium carboxymethylstarch, magnesium stearate and talc, previously passed through a No. 60mesh U.S. sieve (250 μm), are then added to the granules which, aftermixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

Formulation 5

[0363] Capsules, each containing 80 mg of Active Ingredient, are made asfollows: Active Ingredient  80 mg Starch  59 mg Microcrystallinecellulose  59 mg Magnesium stearate  2 mg Total 200 mg

[0364] The Active Ingredient, cellulose, starch, and magnesium stearateare blended, passed through a No. 45 U.S. sieve (355 μm), and filledinto hard gelatin capsules in 200 mg quantities.

Formulation 6

[0365] Suppositories, each containing 225 mg of Active Ingredient, aremade as follows: Active Ingredient  225 mg Saturated fatty acidglycerides 2,000 mg Total 2,225 mg

[0366] The Active Ingredient is passed through a No. 60 U.S. sieve (250μm) and suspended in the saturated fatty acid glycerides previouslymelted using the minimum heat necessary. The mixture is then poured intoa suppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

[0367] Suspensions, each containing 50 mg of Active Ingredient per 5 mldose, are made as follows: Active Ingredient   50 mg Sodiumcarboxymethyl cellulose   50 mg Syrup 1.25 ml Benzoic acid solution 0.10ml Flavor q.v. Color q.v. Purified water to total   5 ml

[0368] The Active Ingredient is passed through a No. 45 mesh U.S. sieve(355 μm) and mixed with the sodium carboxymethyl cellulose and syrup toform a smooth paste. The benzoic acid solution, flavor and color arediluted with a portion of the water and added, with stirring. Sufficientwater is then added to produce the required volume.

Formulation 8

[0369] An intravenous formulation may be prepared as follows: ActiveIngredient   100 mg Isotonic saline 1,000 ml

[0370] The solution of the above materials generally is administeredintravenously to a subject at a rate of 1 ml per minute.

[0371] All of the products of the Examples described below as well asintermediates used in the following procedures showed satisfactory nmrand ir spectra. They also had the correct mass spectral values.

VII. Method of Using the Compounds of the Invention

[0372] This invention is a method for preventing or treating LTB₄induced inflammation in a mammal by contacting the LTB₄ in a mammal withan LTB₄ antagonizing amount of the heterocyclic substituted diphenylcompounds of the invention (as per formula I or II) or a salt, solvateor prodrug of said compounds.

[0373] Another aspect of this invention is a method for preventing ortreating Inflammatory Diseases such as inflammatory bowel disease,septic shock, adult respiratory distress syndrome, panceatitis, trauma,bronchial asthma, allergic rhinitis, rheumatoid arthritis,osteoarthritis, and related diseases which comprises administering to amammal (including a human) a therapeutically effective dose ofheterocyclic substituted diphenyl compounds of the invention (as performula I or II) or a salt, solvate or prodrug of said compounds.

[0374] The specific dose of a compound administered according to thisinvention to obtain therapeutic or prophylactic effects will, of course,be determined by the particular circumstances surrounding the case,including, for example, the compound administered, the route ofadministration and the condition being treated. Typical daily doses willcontain a non-toxic dosage level of the compound of formulae (I). Whenroute of administration is parenteral the dose is about 0.1 to about 100milligrams per day. Intravenous administration can include a continuousdrip. When the route is oral the dose is about 1 to about 1000milligrams per day. Preferred dosages are from about 0.5 to about 300mg/kg per day, most preferably 0.5 to 20 mg/kg, of Active Ingredient maybe administered although it will, of course, readily be understood thatthe amount of the compound or compounds of Formula I actually to beadministered will be determined by a physician, in the light of all therelevant circumstances.

VIII. Assay Method

[0375] The following Assay method was used to evaluate the effects of 3compounds for LTB₄-mediated CD11b upregulation on human neutrophils:

[0376] Note: The Assay procedure described herein was modeled after apreviously published method (viz., Prostaglandins, Leukot, Essent. FattyAcids. 46:265-270. 1992, Biochem. Pharmacol. 49:1683-1690. 1995), thedisclosure of which is incorporated herein by reference.

[0377] The compound C (within the scope of the invention) was evaluatedfor LTB₄ antagonist efficacy. Compounds A and B were control compounds.Compound A is a leukotriene B₄ antagonist known to be effective, butbelonging to a different class of compounds than represented by formulaeI or II, supra. Comparison compound B is structurally similar to thecompounds of the invention, but lacks certain essential functionalgroups necessary for an effective LTB₄ antagonist.

[0378] Approximately 1-2 mg of each compound was weighed and diluted to1 mM in neat dimethyl sulphoxide (DMSO). These stocks were then diluted(using “doubling” dilutions) in assay buffer.

[0379] The assay buffer used throughout the studies consisted of HanksBalanced Salts Solution (HBSS) with added 0.5% bovine serum albumin, lowendotoxin (ICN Biomedicals Catalog #16-980-49). After dissolving the BSAin the HBSS, the buffer was membrane-filtered (0.2μ) before use.

[0380] Human blood was drawn into 3×10 ml EDTA-K₃ Vacutainer tubes,which were pooled and mixed in a 50 ml, blue cap polypropylene tube.Three ml portions of Mono-Poly Resolving medium (MPRM; ICN #16-980-49)were dispensed into 4 separate 13×100 glass disposable tubes. Anadditional 0.3 ml of PBS (phosphate buffered saline) was added to eachtube and mixed with the MPRM by vigorous vortexing. Exactly 3.5 ml ofthe blood was carefully layered on top of the four MPRM-water mixtures.The tubes were gradually accelerated to 400×g and spun at this speed for30 min at room temperature. Tubes were removed from the centrifuge andboth the plasma and top cell (mononuclear) layers were removed anddiscarded. The second layer of cells was carefully collected, pooled andwashed with-assay buffer. The collected neutrophil cell preparation wasthen spun at 400×g for 5 min and re-washed once again. The cells wereresuspended in assay buffer and counted using a Cell-Dyn 1600 cellcounter (Abbott Diagnostics Co.). They were then resuspended in bufferat 9×10⁶ cells/ml and held briefly for addition in a later step of theassay.

[0381] LTB4, (Biomol; ETOH stock @ 148.5 μM) was diluted to a 3.9 μMstock in assay buffer by dilution of 10 μl ETOH stock+371 μl assaybuffer, mixed well and further diluted 1:100 (100 μl+9.9 ml buffer) tomake a use stock of 39 nM in buffer for later use. The finalconcentration of LTB₄ (3 nM) was determined after several experimentalruns.

[0382] Exactly 10 μl of each putative compound/dilution and 10 μl ofanti-CD11b-FITC (FITC=Fluorescein Isothiocyanate; Biosource Intl.,#AHS1148) was carefully added to the bottom of 12×75 mm polypropylenetubes (Falcon #2063) as determined by the experimental design. Followingthis, 100 μl of the human neutrophil preparation (9E6/ml) was added andmixed well by vortexing. The compound/cell mixtures were incubatedtogether for 15 minutes at room temperature. Following this incubation,10 μl of diluted LTB₄ stock was added (to make 3 nM final LTB₄concentration), mixed by vortexing and incubated in a 37° C. shakingwater bath for 30 min. Following this the tubes were immediately placedon ice for 10 minutes. Following this 1 ml of diluted BD FACS Lyse(Becton Dickinson Fluorescense Activated Cell Sorting Lyse), was addedto the tubes and vortexed. 10 minutes later the tubes were spun at 400×gat room temperature. After centrifugation, the tubes were aspirated andre-suspended in 1.0 ml of 1% paraformaldehyde solution.

[0383] The samples were then analyzed for fluorescence intensity (linearscale) using an EPICS XL flow cytometer and the “Mo-1 IsolatedNeutrophil” protocol.

[0384] The mean fluorescence intensity (MFI) for each sample wascomputed using WinList software and expressed as percentage of maximumMFI.Microsoft Excel and further graphed and analyzed using linearregression. TABLE 1 Assay Results Compounds of the Invention Example No.CD11b/CD18 IC50 (nM) 1 480 2 5880 3 353; 339 4 74; 117 5 175; 223 6 2607 2020; 3790 8 >50000 9 23; 20 10 14; 4.4; 8.3 11 620; 2560; 1010 1210000; 5700 13 39; 54 14 31; 30 15 27 16 1080; 837 17 11; 5.6; 8

[0385] TABLE 2 Assay Results for Comparison Compounds Compound IC-50(nM) ± SEM A* 1.7 ± 0.25 B not active

[0386] Compound A—a known LTB₄ antagonist (see, Example 66 of U.S. Pat.No. 5,462,954) which is not heterocycle substituted and is not an aspectof this invention:

[0387] Compound B—a control compound related to Compound A and not anaspect of this invention, represented by the formula:

1-17. (canceled)
 18. The compound of claim 1 wherein the R1, R2, R3 andR4 groups for substitution in formula (I) are selected from thefollowing variables coded R01 thru R16 R variables Combination R1 groupR2 group R3 group R4 group Code choice choice choice choice R01 R1 R2 R3R4 R02 R1 R2 R3 PG1-R4 R03 R1 R2 PG1-R3 R4 R04 R1 R2 PG1-R3 PG1-R4 R05R1 PG1-R2 R3 R4 R06 R1 PG1-R2 R3 PG1-R4 R07 R1 PG1-R2 PG1-R3 R4 R08 R1PG1-R2 PG1-R3 PG1-R4 R09 PG1-R1 R2 R3 R4 R10 PG1-01 R2 R3 PG1-R4 R11PG1-R1 R2 PG1-R3 R4 R12 PG1-R1 R2 PG1-R3 PG1-R4 R13 PG1-R1 PG1-R2 R3 R4R14 PG1-R1 PG1-R2 R3 PG1-R4 R15 PG1-R1 PG1-R2 PG1-R3 R4 R16 PG1-R1PG1-R2 PG1-R3 PG1-R4

and; the Y1, Y2, and Y3 groups for substitution in formula (I) areselected from the following variables coded Y01 thru Y27: Y variablescombination Y1 group code choice Y2 group choice Y3 group choice Y01 Y1Y2 Y3 Y02 Y1 Y2 PG1-Y3 Y03 Y1 Y2 PG2-Y3 Y04 Y1 PG1-Y2 Y3 Y05 Y1 PG2-Y2Y3 Y06 Y1 PG1-Y2 PG1-Y3 Y07 Y1 PG1-Y2 PG2-Y3 Y08 Y1 PG2-Y2 PG1-Y3 Y09 Y1PG2-Y2 PG2-Y3 Y10 PG1-Y1 Y2 Y3 Y11 PG1-Y1 Y2 PG1-Y3 Y12 PG1-Y1 Y2 PG2-Y3Y13 PG1-Y1 PG1-Y2 Y3 Y14 PG1-Y1 PG1-Y2 PG1-Y3 Y15 PG1-Y1 PG1-Y2 PG2-Y3Y16 PG1-Y1 PG2-Y2 Y3 Y17 PG1-Y1 PG2-Y2 PG1-Y3 Y18 PG1-Y1 PG2-Y2 PG2-Y3Y19 PG2-Y1 Y2 Y3 Y20 PG2-Y1 Y2 PG1-Y3 Y21 PG2-Y1 Y2 PG2-Y3 Y22 PG2-Y1PG1-Y2 Y3 Y23 PG2-Y1 PG1-Y2 PG1-Y3 Y24 PG2-Y1 PG1-Y2 PG2-Y3 Y25 PG2-Y1PG2-Y2 Y3 Y26 PG2-Y1 PG2-Y2 PG1-Y3 Y27 PG2-Y1 PG2-Y2 PG2-Y3

and; the X and Z groups and the n variable for substitution in formula(I) are selected from the following variables coded XZn01 thru XZn24:XZn variables Z combination X group Group n integer code choice Choicegroup choice XZn01 X Z n XZn02 X Z PG1-n XZn03 X Z PG2-n XZn04 X PG1-Z nXZn05 X PG2-Z n XZn06 X PG3-Z n XZn07 X PG1-Z PG1-n XZn08 X PG2-Z PG1-nXZn09 X PG3-Z PG1-n XZn10 X PG1-Z PG2-n XZn11 X PG2-Z PG2-n XZn12 XPG3-Z PG2-n XZn13 PG1-X Z n XZn14 PG1-X Z PG1-n XZn15 PG1-X Z PG2-nXZn16 PG1-X PG1-Z n XZn17 PG1-X PG2-Z n XZn18 PG1-X PG3-Z n XZn19 PG2-XPG1-Z PG1-n XZn20 PG2-X PG2-Z PG1-n XZn21 PG2-X PG3-Z PG1-n XZn22 PG2-XPG1-Z PG2-n XZn23 PG2-X PG2-Z PG2-n XZn24 PG2-X PG3-Z PG2-n

19-22. (canceled)
 23. A pharmaceutical composition which comprises atherapeutically effective amount of a compound according to claim 19 anda pharmaceutically acceptable carrier or diluent.
 24. A method for thetreatment or prevention of Inflammatory Diseases, which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a compound according to claim
 18. 25. A method for in vivoinhibition of leukotriene B₄ in a mammal in need thereof, whichcomprises administering to said mammal a therapeutically effectiveamount of a compound according to claim
 18. 26. The method of claim 25wherein the route of administration is oral and the dose is about 1 toabout 1000 milligrams per day.
 27. The method of claim 25 wherein theroute of administration is parenteral and the dose is about 0.1 to about100 milligrams per day. 28-29. (canceled)